J Transl Med [JOURNAL]
Sun
200 papers
The oral microbiome is associated with the diagnosis, prognosis and radiotherapy sensitivity of esophageal cancer.
Li L, Li L, Yang Y … +9 more , Wang C, Lan Z, Liu J, Zhu X, Zhao C, Yang M, Ma Y, Liu Y, Ren Z
J Transl Med · 2026 Jun · PMID 42286580 · Full text
BACKGROUND: Esophageal cancer (EC) is a leading cause of cancer-related mortality worldwide and early detection strategies and precise postoperative interventions must be developed. However, the identification of noninva...
BACKGROUND: Esophageal cancer (EC) is a leading cause of cancer-related mortality worldwide and early detection strategies and precise postoperative interventions must be developed. However, the identification of noninvasive biomarkers for the diagnosis and prognosis remains limited. METHODS: We performed 16S rRNA gene sequencing on tongue-coating samples from 440 participants, including 157 EC patients, 167 healthy controls (HCs) and 120 EC patients who received radiotherapy. We characterized the oral microbiome and constructed microbial diagnostic and prognostic classifiers. Furthermore, the oral microbiome of EC who received radiotherapy (n = 120) was characterized. RESULTS: The oral microbial diversity of EC patients was increased, with differences in the microbial community between EC patients and HCs. In EC, the genera Veillonella, Streptococcus and Actinomyces were enriched, whereas Porphyromonas and Rothia were depleted. The classifier based on six optimal microbial markers was constructed using random forest algorithm and achieved area under the curves (AUCs) of 93.69% and 95.18% in discovery and validation groups, respectively. After radiotherapy, the oral microbial diversity and richness were significantly reduced. The prevalence of opportunistic pathogens, including Fusobacterium and Porphyromonas, decreased, whereas the prevalence of Streptococcus and Actinomyces increased in EC patients after radiotherapy. Through six months of follow-up, patients were categorized into a progression group (PG) (n = 26) and a nonprogression group (NPG) (n = 106) based on the presence of tumor recurrence, metastasis, and death. A prognostic model based on 13 selected amplicon sequence variants (ASVs) of the oral microbiome was constructed, with an AUC of 99.29%. The random forest analysis identified six key differential ASVs between the PG and the NPG, including Fusobacterium and Gemella. Additionally, twenty-five ASVs associated with nine clinical indicators were identified. CONCLUSIONS: Our study provides a comprehensive characterization of the oral microbiome in both EC patients and EC patients after radiotherapy, highlighting the potential of the oral microbiome as noninvasive biomarkers for determining the diagnosis and prognosis of EC.
Dihydrotanshinone I as a novel signal transducer and activator of transcription 3 inhibitor for glioblastoma treatment.
Cheng KW, Zhou SJ, Zeng J … +8 more , Zhang YR, Jin BQ, Wang P, He LY, Qi XC, Liu XD, Yu LS, Zhang YX
J Transl Med · 2026 Jun · PMID 42277880 · Full text
BACKGROUND: Among tumors affecting the central nervous system (CNS), glioblastoma multiforme (GBM) is the most aggressive and lethal form. Given the complex mechanisms of the CNS and the blood-brain barrier (BBB), effect...
BACKGROUND: Among tumors affecting the central nervous system (CNS), glioblastoma multiforme (GBM) is the most aggressive and lethal form. Given the complex mechanisms of the CNS and the blood-brain barrier (BBB), effective therapies for GBM remain limited. To identify potential therapeutic candidates for glioma, we developed a small-molecule library to screen for compounds with potent anti-proliferative effects and BBB permeability. The mechanisms underlying their anti-glioma activity were further elucidated to provide insights into new treatment strategies. METHODS: A library of small molecules was screened to identify agents that significantly inhibit glioma cells activity. The effects of the lead compound (Dihydrotanshinone I, DHT) on glioma progression were evaluated through a series of experimental approaches, including cell counting kit-8 assays, cell cycle analysis, apoptosis detection, wound healing, transwell migration, reactive oxygen measurement, subcutaneous xenograft mouse models, and intracranial orthotopic tumor models. To elucidate the underlying mechanisms, network pharmacology and transcriptomic analyses were employed. The mechanism of DHT in glioma pathogenesis was further validated using bioinformatics analyses and clinical glioma tissue samples. RESULTS: Based on pharmacokinetic evaluation, DHT was found to traverse the BBB, indicating its capacity to reach the cerebral parench. In vitro and in vivo experiments demonstrated that DHT significantly suppresses glioma growth and progression. Mechanistic analyses using network pharmacology and RNA sequencing revealed that DHT induces glioma cell apoptosis by inhibiting the Janus kinase-signal transducer and activator of transcription 3 (STAT3) signaling pathway, increasing intracellular reactive oxygen species levels and triggering intrinsic apoptotic cascades. Furthermore, bioinformatic analyses of clinical cohorts coupled with validation in patient-derived glioma specimens confirmed that elevated STAT3 expression was correlated with unfavorable prognosis and was significantly increased in patients with high-grade glioma. CONCLUSIONS: This study demonstrates that, in addition to its role as a key contributor to glioma malignancy and a prognostic marker, STAT3 is also a target of DHT, highlighting its potential as a promising therapeutic candidate for treating GBM.
CT-based habitat analysis combined with multi-channel deep learning for predicting early recurrence after pancreatic cancer resection: a multicenter study.
Peng J, Wu H, Chen X … +9 more , Ou Z, Yang X, Ma R, Liu Y, Xu X, Du C, Li S, You Y, Li J
J Transl Med · 2026 Jun · PMID 42277870 · Full text
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with high early recurrence rates after curative resection. Current prediction methods, based on clinicopathological features or conventional radio...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with high early recurrence rates after curative resection. Current prediction methods, based on clinicopathological features or conventional radiomics, often fail to capture intratumoral heterogeneity (ITH), a key driver of recurrence. Computed tomography (CT)-based habitat analysis quantifies ITH by identifying phenotypically distinct tumor subregions, while deep learning (DL) can extract complex imaging patterns. Their integration may improve recurrence risk assessment. This study aimed to develop and validate a fusion model that integrates CT-based habitat analysis, a 2.5D convolutional neural network (CNN)-Transformer DL framework, and clinicopathological features to noninvasively predict early recurrence (within one year) risk after PDAC resection. METHODS: In this multicenter retrospective study, 346 patients with resected PDAC were included from four institutions. Tumors were segmented into three habitat subregions via unsupervised K‑means clustering. Radiomic features from these subregions constructed the HabitatAll model. In parallel, a DL model was built using a 2.5D CNN-Transformer architecture. Predictive scores from both models were integrated with key clinicopathological variables through ridge regression to develop the fusion model (HADLC). Model interpretability was examined using SHAP (SHapley Additive exPlanations) and Grad‑CAM (Gradient‑weighted Class Activation Mapping). Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, calibration curves, and decision curve analysis (DCA). RESULTS: The HADLC model showed superior predictive ability, achieving AUCs of 0.977 (training), 0.916 (internal test), and 0.838-0.866 (external validation), outperforming the standalone HabitatAll, DL, and Clinic models. It demonstrated good calibration and provided higher net clinical benefit across most decision thresholds. Interpretability analyses revealed key imaging phenotypes linked to aggressive tumor biology. CONCLUSION: The HADLC model effectively integrates multimodal information to accurately assess early postoperative recurrence risk in PDAC, providing a robust, non-invasive imaging biomarker to potentially guide personalized treatment.
Long-term polystyrene nanoplastics exposure aggravates retinal inflammation and photoreceptor degeneration through microglial SPP1 signaling and neutrophil extracellular traps formation.
Zhou W, Chen X, Li J … +1 more , He J
J Transl Med · 2026 Jun · PMID 42277857 · Full text
BACKGROUND: Micro/nanoplastics (MNPs), as emerging environmental contaminants, present a growing concern for human health. This study aims to investigate the effects of polystyrene nanoplastics (PS-NPs) exposure on retin...
BACKGROUND: Micro/nanoplastics (MNPs), as emerging environmental contaminants, present a growing concern for human health. This study aims to investigate the effects of polystyrene nanoplastics (PS-NPs) exposure on retinal pathology and underlying mechanisms. METHODS: Retinal detachment (RD) model was established on adult mice following PS-NPs exposure (10 and 50 mg/L) through drinking water for two months. In vitro, oxygen glucose deprivation (OGD) model was established on BV2 microglia-661W photoreceptor co-culture system following PS-NPs exposure (100 mg/L) for 24 h. SPP1 neutralizing antibody and recombinant protein were administrated by subretinal injection. DNase I and Cl-amidine were utilized to achieve neutrophil extracellular traps (NETs) inhibition. Electroretinogram was used to assess retinal function. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunofluorescent staining, western blot analysis and enzyme activity assays were used to analyze photoreceptor apoptosis, microglial responses and oxidative stress. Microglia were purified with CD11b MicroBeads. Transcriptomic profiles of PS-NPs-exposed microglia and human retinas of proliferative vitreoretinopathy (PVR) were analyzed. RESULTS: PS-NPs were able to breach the blood-retina barrier, disrupt phototransduction, aggravate oxidative stress and apoptosis in RD-induced photoreceptor degeneration model dose-dependently. Mechanistically, PS-NPs exposure triggered retinal inflammation, microglial activation and microglial SPP1-mediated peripheral neutrophil recruitment. SPP1 neutralization mitigated PS-NPs-aggravated chemokine secretion, neutrophil infiltration and NETs formation. Recombinant SPP1 protein treatment heightened neutrophil-driven retinal damage, while this could be partially reversed by chemokine receptor inhibition. NETs inhibition alleviated PS-NPs-exacerbated microglial proinflammatory activation and photoreceptor degeneration. Furthermore, transcriptomic profiling showed parallels between PS-NPs-exposed microglia and human PVR specimens in SPP1 signaling and stress/stimulus response pathways. CONCLUSIONS: Our findings demonstrated that PS-NPs exposure aggravated retinal inflammation and photoreceptor degeneration by microglial SPP1 signaling activation and NETs formation, underscoring new insights into the effects and potential targets of MNPs exposure on retinal disorders.
TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients.
Damiano C, Tarallo A, Strollo S … +8 more , Minopoli N, Valanzano A, Assunto A, Tuzzi MR, Brunetti-Pierri N, Ballabio A, Sorrentino NC, Parenti G
J Transl Med · 2026 Jun · PMID 42277847 · Full text
OBJECTIVE: Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of t...
OBJECTIVE: Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of treatment for PD is enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Despite significant success of ERT in correcting some disease manifestations, limitations of its efficacy have emerged, due to several factors. Poor expression or abnormal intracellular distribution of the cation-independent mannose-6-phosphate receptor (M6PR) at the plasma membrane of specific cells has been identified as one of these factors. Here, we investigated whether activation of Transient Receptor Potential Mucolipin 1 (TRPML1) synergizes with ERT. TRPML1 is a lysosomal ion channel that has been shown to induce multiple effects, including regulation of calcium homeostasis, stimulation of autophagy, activation of lysosomal biogenesis and exocytosis, enhancement of vesicle and membrane trafficking. METHODS: We studied the effects of two TRPML1 agonists in cultured fibroblasts from Pompe disease patients. Specifically, we analyzed M6PR availability at the plasma membrane of control and mutant cells, level of correction of GAA activity by rhGAA, processing and lysosomal trafficking of the recombinant enzyme. RESULTS: Treatment with two TRPML1 agonist drugs increased M6PR total amounts and its availability at the plasma membrane and improved M6PR intracellular recycling. The improvements in M6PR distribution translated into better correction of GAA activity in cells incubated with rhGAA and in improved lysosomal trafficking and processing of the recombinant enzyme. CONCLUSION: These data provide in vitro proof-of-concept evidence supporting the combination of ERT with pharmacological manipulation of secondarily altered M6PR distribution as a strategy to obtain better exposure of cells to therapeutic enzymes.
Impact of antinuclear and antiphospholipid antibodies on ART outcomes in women with recurrent reproductive failure.
Fang QY, Gan DH, Chen RY … +3 more , Zhu KH, Huang J, Lian F
J Transl Med · 2026 Jun · PMID 42277805 · Full text
BACKGROUND: Recurrent reproductive failure (RRF), encompassing repeated implantation failure and pregnancy loss, remains a major challenge in assisted reproductive technology (ART). Autoimmune factors have been implicate...
BACKGROUND: Recurrent reproductive failure (RRF), encompassing repeated implantation failure and pregnancy loss, remains a major challenge in assisted reproductive technology (ART). Autoimmune factors have been implicated in adverse reproductive outcomes, but the combined impact of antinuclear antibodies (ANA) and antiphospholipid antibodies (aPL) on ART success in women with RRF is unclear. METHODS: This retrospective cohort study analyzed 682 women with RRF who underwent IVF or ICSI between April 2019 and April 2024. Participants were classified into four groups based on ANA and aPL status. Clinical characteristics, laboratory indices, and ART outcomes were compared. Univariable and multivariable logistic regression analyses were conducted to identify predictors of live birth. RESULTS: Live birth rates differed significantly across groups (p = 0.001), with the ANA-/aPL- group showing the highest rate (36.3%) and lower rates in women positive for either or both autoantibodies. Clinical pregnancy rates were also lower in the ANA+/aPL+ group (30.6% vs. 49.8%, p = 0.050). Multivariable analysis confirmed ANA positivity (adjusted OR 0.57, 95% CI 0.38-0.86) and longer infertility duration as independent predictors of reduced live birth rates. No significant differences were observed between single and multiple ANA specificities in terms of reproductive outcomes. CONCLUSIONS: The concurrent presence of ANA and aPL is associated with significantly poorer IVF outcomes in women with unexplained RRF. These findings suggest that comprehensive autoantibody profiling may help identify a specific high-risk subset of RRF patients. Further prospective studies are warranted to determine whether this subgroup benefits from targeted immunomodulatory interventions.
Translational potential of GMP-grade human umbilical cord-derived mesenchymal stem cells (UC-MSCs) in traumatic spinal cord injury: a preclinical study in rat.
Han Z, Yu H, Du W … +9 more , Gao Y, Pan K, Jia H, Zhao M, Wei Z, Yan S, Wang Y, Li Z, Ni G
J Transl Med · 2026 Jun · PMID 42271443 · Full text
BACKGROUND: Traumatic spinal cord injury (SCI) often results in irreversible motor, sensory, and autonomic dysfunction, with limited effective treatment options currently available. Human umbilical cord-derived mesenchym...
BACKGROUND: Traumatic spinal cord injury (SCI) often results in irreversible motor, sensory, and autonomic dysfunction, with limited effective treatment options currently available. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) represent a promising therapeutic approach due to their immunomodulatory, neuroprotective, and regenerative properties. However, the lack of comprehensive efficacy data using GMP-grade cells, uncertainty regarding optimal dosing, and incomplete understanding of their mechanisms have hindered clinical translation. METHODS: A T10-level SCI model was established in 50 Sprague‒Dawley rats using Allen's weight-drop method. The animals were randomly divided into five groups: Sham, Model, Solvent, Low-dose (1 × 10⁷ cells/kg), and High-dose (3 × 10⁷ cells/kg). GMP-grade human UC-MSCs were administered intravenously on post-injury days 3 and 7. A comprehensive evaluation was performed using BBB scoring for locomotor function, MRI for lesion volume assessment, histopathological examination (H&E and Nissl staining), ELISA for serum cytokine quantification, immunofluorescence for GFAP and GAP-43 expression, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs), in vivo UC-MSCs tracking, and sRNA sequencing of human UC-MSC-derived exosomes. RESULTS: The high-dose UC-MSC treatment demonstrated significant therapeutic effects, including: improved hindlimb motor function (BBB scores from days 7 to 21), reduced spinal cord lesion volume, attenuated pathological damage (decreased cavity formation, preserved neuronal morphology, increased neuron density), and suppressed acute inflammation (reduced TNF-α and IL-6 levels). Additionally, high-dose treatment decreased astrocyte activation (reduced GFAP expression), enhanced neuronal plasticity (increased GAP-43), modulated immune cell populations (increased naïve CD4⁺/CD8⁺ T cells, decreased memory B cells), and downregulated SCI-activated genes (including Kras and Nfkb1). In vivo tracking revealed initial pulmonary accumulation of UC-MSCs followed by clearance within 3 days. sRNA sequencing of human UC-MSC-derived exosomes identified several human-derived miRNAs (hsa-miR-21-5p, hsa-let-7a-5p, hsa-miR-10b-5p, hsa-miR-451a, and hsa-miR-10a-5p) potentially involved in the repair process. CONCLUSIONS: GMP-grade human UC-MSCs exert therapeutic effects in SCI through multiple mechanisms, including anti-inflammatory actions, inhibition of glial scarring, neuroprotection, and immune modulation. The high-dose regimen (3 × 10⁷ cells/kg) demonstrated superior efficacy across functional, structural, and molecular endpoints. This study provides critical preclinical evidence supporting the clinical application of UC-MSCs for SCI treatment and elucidates their underlying therapeutic mechanisms.
Mechanisms of actin-binding proteins in glycolysis-cytoskeleton coupling.
Zhang Z, Ma N, Zhang N … +7 more , Wang X, Lu Y, Sheng C, Zhang J, Zhao X, Jiao Y, Wang A
J Transl Med · 2026 Jun · PMID 42271387 · Full text
BACKGROUND: The spatiotemporal coordination between actin cytoskeleton dynamics and glycolytic metabolism represents a critical frontier at the intersection of mechanobiology and cellular metabolism. While a bidirectiona...
BACKGROUND: The spatiotemporal coordination between actin cytoskeleton dynamics and glycolytic metabolism represents a critical frontier at the intersection of mechanobiology and cellular metabolism. While a bidirectional relationship between these processes is increasingly recognized, the underlying mechanistic coupling-particularly the role of actin-binding proteins (ABPs)-remains incompletely understood. This knowledge gap significantly limits our comprehensive understanding of mechano-metabolic cross-regulation. MAIN CONTENT: Here, we synthesize recent advancements in cytoskeletal dynamics and metabolic regulation to propose an ABP-mediated "metabolism-cytoskeleton" bidirectional coupling axis as a conceptual framework. By delineating the signaling cascades within this framework, we critically examine how ABPs function as key mediators that coordinate cytoskeletal remodeling with glycolytic flux in specific cellular contexts. Furthermore, we highlight recent mechanistic insights, evaluate prevailing controversies, and identify unresolved scientific questions that warrant future investigation. CONCLUSION: The proposed bidirectional "metabolism-cytoskeleton" feedback model conceptualizes the continuum from extracellular mechanotransduction to terminal cellular behavior. By expanding upon traditional unidirectional models, this framework provides a conceptual scaffold for understanding mechano-metabolic crosstalk. Additionally, it explores potential context-dependent therapeutic implications for diseases characterized by aberrant cytoskeletal and metabolic states, such as specific models of cancer and fibrosis.
CSF2 drives radiation-induced lung injury by eliciting PADI4-high pathogenic neutrophils.
Wang Y, Abulaihaiti M, Pan Y … +2 more , Zhang J, Shao C
J Transl Med · 2026 Jun · PMID 42271382 · Full text
BACKGROUND: Radiation-induced lung injury (RILI) represents a severe, therapy-refractory complication of thoracic radiotherapy. Although neutrophils have been implicated in RILI pathogenesis, the specific pathogenic subs...
BACKGROUND: Radiation-induced lung injury (RILI) represents a severe, therapy-refractory complication of thoracic radiotherapy. Although neutrophils have been implicated in RILI pathogenesis, the specific pathogenic subsets and the molecular mechanisms governing their recruitment and functional specialization remain elusive. This study aims to decode the crosstalk between damaged epithelial cells and neutrophils in the RILI microenvironment. METHODS: We established a murine RILI model using 17 Gy thoracic irradiation and performed integrated single-cell RNA sequencing (scRNA-seq) and bulk transcriptome profiling to map the immune landscape. Neutrophil heterogeneity and developmental trajectories were analyzed using pseudotime algorithms. Mechanistic investigations used an indirect co-culture system of irradiated lung epithelial cells and HL-60 neutrophil-like cells, recombinant CSF2, CSF2-neutralizing antibodies, and in vivo anti-GM-CSF blockade. The therapeutic potential of PADI4 inhibition was evaluated using GSK484 in RILI mice, followed by histopathological, molecular, immunofluorescence, ELISA, and bulk RNA-seq analyses. RESULTS: Integrated multi-omics analyses identified PADI4 as a central neutrophil-associated molecule in RILI, with preferential enrichment in immature, NETosis-prone neutrophil subsets mobilized during emergency granulopoiesis. Among PAD family members, PADI4 showed the most prominent neutrophil-restricted and injury-responsive expression pattern. Mechanistically, radiation-damaged epithelial cells secrete CSF2, which induces a PADI4-high activated myeloid phenotype in vitro; conversely, CSF2 neutralization attenuated this response. In vivo GM-CSF blockade reduced PADI4-positive neutrophil infiltration and lung injury severity. Pharmacological PADI4 inhibition with GSK484 suppressed citrullinated histone H3 generation, NETosis-associated programs, neutrophil chemotaxis modules, and tissue damage in the RILI model. CONCLUSIONS: This study delineates an epithelial-myeloid damage-response circuit in RILI and identifies CSF2-driven PADI4 activation in pathogenic neutrophils as a therapeutically actionable mechanism.
Single-cell T-cell landscape in atherosclerosis: implications for targeted therapy and beyond.
Luo R, Liu S, Ouyang X … +2 more , Zhou E, Jiang L
J Transl Med · 2026 Jun · PMID 42271375 · Full text
BACKGROUND: Atherosclerosis (AS) progression is profoundly influenced by dynamic T-cell heterogeneity and functional plasticity. MAIN BODY: This review consolidates the latest insights derived from single-cell transcript...
BACKGROUND: Atherosclerosis (AS) progression is profoundly influenced by dynamic T-cell heterogeneity and functional plasticity. MAIN BODY: This review consolidates the latest insights derived from single-cell transcriptomic technologies, which are transforming our understanding of the role of the immune system in plaque pathogenesis. Recent evidence revealed previously unrecognized T-cell subsets within murine and human atherosclerotic lesions, distinguished by unique transcriptional profiles and adaptability driven by their microenvironment. Spatial mapping techniques have revealed compartment-specific distributions of T cells across vascular layers, whereas temporal analyses have highlighted age-related changes in the balance between effector and regulatory functions. Notably, single-cell resolution delineated transitional states between cytotoxic and regulatory lineages, suggesting that local inflammatory signals play a crucial role in determining T-cell fate. Despite these advancements, challenges remain in fully understanding T-cell lineage commitment, plasticity, and interactions with vascular niches. The integration of emerging multiomics approaches and spatial transcriptomics holds promise for addressing these challenges, providing a roadmap for novel therapeutic strategies. This includes not only the development of targeted immunotherapies but also the identification of key molecular targets for drug intervention and precision diagnostics, ultimately broadening the horizon for clinical applications in atherosclerosis. CONCLUSIONS: This review synthesizes single-cell RNA sequencing-driven discoveries in AS immunology, highlighting the heterogeneity and plasticity of plaque T-cell subsets. These insights lay the groundwork for developing targeted immunotherapies and identifying novel molecular targets and diagnostic biomarkers, ultimately advancing precision medicine for AS patients.
Gut fungal signatures in colorectal cancer and their potential for supporting diagnosis: a multi-cohort metagenomic analysis.
Zhang Z, Lu T, Dong B … +14 more , Liu J, Zhang Y, Li S, Liu H, Li X, Guan T, Guo H, Yan Q, Lei Z, Yu X, Wang L, Kang J, Li L, Zhao D
J Transl Med · 2026 Jun · PMID 42271362 · Full text
BACKGROUND: Colorectal cancer (CRC) is influenced by host factors and environmental exposures that shape gut microbial ecosystems. Although bacterial and viral alterations in CRC have been widely investigated, the role o...
BACKGROUND: Colorectal cancer (CRC) is influenced by host factors and environmental exposures that shape gut microbial ecosystems. Although bacterial and viral alterations in CRC have been widely investigated, the role of gut fungi remains underexplored, partly because of their low biomass and the limited availability of well-curated fungal reference genomes. METHODS: We conducted a large-scale metagenomic analysis across 9 publicly available cohorts comprising 1,433 fecal samples to characterize CRC-associated fungal alterations and fungal-bacterial co-abundance patterns. The predictive value of microbial signatures was assessed using LASSO and random forest models, with external validation performed in 6 independent cohorts comprising 272 samples. RESULTS: Multi-cohort analysis revealed CRC-associated alterations in gut fungal community structure and selected diversity measures. Differential abundance analysis identified 15 fungal species with recurrent changes across cohorts. Among them, Saccharomyces cerevisiae c86 and Trichophyton rubrum c61 showed predominant enrichment in healthy controls, whereas Barnettozyma c122 and Pseudopithomyces c302 showed predominant enrichment in CRC. Fungal-only models exhibited limited standalone predictive capacity. However, integrating fungal features with bacterial biomarkers modestly improved CRC prediction performance compared with bacterial-only models. In external validation, the random forest-based fungal-bacterial model increased the mean AUC from 0.722 to 0.762, with improved AUCs in 5 of the 6 validation cohorts. CONCLUSIONS: This study suggests that CRC is associated with gut fungal dysbiosis and supports the exploratory value of gut fungal signatures as adjunctive features in microbiome-based CRC prediction models. These findings highlight the importance of incorporating fungal communities into CRC microbiome research while emphasizing the need for prospective and mechanistic validation.
Gut mycobiota alteration contributes to the pathogenesis of Pneumocystis pneumonia.
Chen Y, Kang H, Yang B … +7 more , Feng L, Tong R, Zhao Z, Liang L, Li X, Liu X, Tong Z
J Transl Med · 2026 Jun · PMID 42271360 · Full text
BACKGROUND: Pneumocystis is an opportunistic fungal pathogen that causes life-threatening pneumonia in immunocompromised hosts, with increasing incidence in HIV-negative individuals. Although the gut mycobiota has emerge...
BACKGROUND: Pneumocystis is an opportunistic fungal pathogen that causes life-threatening pneumonia in immunocompromised hosts, with increasing incidence in HIV-negative individuals. Although the gut mycobiota has emerged as a critical regulator of distal immunity, its role in HIV-negative Pneumocystis pneumonia (PCP) remains entirely unexplored. METHODS: We established a murine model of Pneumocystis murina infection and performed full-length internal transcribed spacer (ITS) sequencing to characterize longitudinal changes in gut fungal communities over five weeks. Untargeted metabolomics was conducted on plasma samples to identify systemic metabolic alterations. To investigate causality, gut fungal communities were depleted using fluconazole, and fecal microbiota transplantation (FMT) was performed in germ-free mice to assess the functional role of gut fungi in modulating pulmonary immune responses. RESULTS: While α diversity of the gut mycobiota remained unchanged, β diversity analysis revealed significant structural alterations beginning week 3 (w3) post-infection, coinciding with peak pulmonary fungal burden. Linear discriminant analysis effect size identified Purpureocillium lilacinum and Talaromyces verruculosus as enriched opportunistic taxa. Untargeted metabolomics demonstrated marked metabolic reprogramming at w3, with significant perturbations in glycine, serine, and threonine metabolism, as well as the tricarboxylic acid cycle. Fluconazole-mediated depletion of gut fungi significantly increased pulmonary Pneumocystis burden and exacerbated lung inflammation, accompanied by reduced pulmonary Th1 cell responses. Critically, FMT from fluconazole-treated donors into germ-free mice recapitulated the exacerbated phenotype, confirming that gut fungal dysbiosis is sufficient to impair Th1-mediated antifungal immunity and worsen disease severity. CONCLUSIONS: This study establishes, for the first time, that gut fungal dysbiosis actively contributes to the pathogenesis of HIV-negative PCP via the gut-lung axis. Our findings reveal that commensal gut fungi support pulmonary Th1 immune responses essential for controlling PCP, and their disruption exacerbates disease. These results provide new insights into the gut mycobiota as a potential therapeutic target in PCP and caution against indiscriminate antifungal use in susceptible populations.
ProptoView: AI-based digital exophthalmometry using multi-view facial images in a multinational validation study.
Lei C, Song S, Fan J … +18 more , Pandiyan PS, Ding J, Wattanaphanich S, Liu X, Lu W, Wei D, Zhang S, Zhou M, Su J, Lyu X, Zhuang W, Song X, Xu B, Ding X, Sintuwong S, Yip CC, Dang K, Zhou H
J Transl Med · 2026 Jun · PMID 42271356 · Full text
BACKGROUND: Accurate proptosis measurement is vital for managing thyroid eye disease (TED) and other orbital conditions. However, current approaches have certain limitations: the Hertel exophthalmometer is convenient but...
BACKGROUND: Accurate proptosis measurement is vital for managing thyroid eye disease (TED) and other orbital conditions. However, current approaches have certain limitations: the Hertel exophthalmometer is convenient but imprecise, while computed tomography (CT) is accurate but costly and exposes patients to radiation. METHODS: We developed ProptoView, an AI-based digital exophthalmometer, using 5676 images from 2516 eyes across 1258 visits of 763 TED patients with CT and Hertel measurements. For external validation, we used an additional 644 images from 648 eyes of 324 patients with TED and other orbital diseases, collected across three countries and five hospitals. Patients provided up to five images from four views. A three-stage deep learning approach, optimized with Adam and validated via five-fold cross-validation, helped develop three AI models: single-view, multi-view, and dynamic input. RESULTS: Compared with CT, the single-view model achieved an intraclass correlation coefficient (ICC) of 0.859, slightly lower than the Hertel exophthalmometer's ICC of 0.888. The multi-view model achieved an ICC of 0.890, surpassing the Hertel exophthalmometer (0.871). The dynamic input model achieved the highest accuracy with an ICC of 0.901. Among two-view combinations, pairing the frontal view with another angle showed the highest agreement when paired with the upward gaze view (ICC = 0.855). In external validation, ProptoView showed robust concordance with the Hertel exophthalmometer (ICC = 0.845), comparable to its agreement in the development dataset. Additionally, ProptoView reduced misclassification at the 19-mm threshold (14.7% vs. 20.5% with the Hertel exophthalmometer). CONCLUSION: ProptoView provides an accurate, non-contact, and cost-effective solution for proptosis measurement. Its flexibility and precision suggest significant potential for streamlining clinical workflows and enabling telemedicine applications.
Prolonged linezolid therapy induces progressive mitochondrial dysfunction in human peripheral blood mononuclear cells.
Martínez-Guitián M, Cajade-Pascual F, Castro-Fernández DC … +9 more , Cuartero-Martínez A, Nogueiras R, Fernández-Castro I, Molinos-Castro S, Ortea I, Zarra-Ferro I, González-Barcia M, Fernández-Ferreiro A, Mondelo-García C
J Transl Med · 2026 Jun · PMID 42265784 · Full text
BACKGROUND: Linezolid commonly causes hematologic toxicity, especially thrombocytopenia, during extended treatment. This effect is linked to the inhibition of mitochondrial protein synthesis, which impairs oxidative phos...
BACKGROUND: Linezolid commonly causes hematologic toxicity, especially thrombocytopenia, during extended treatment. This effect is linked to the inhibition of mitochondrial protein synthesis, which impairs oxidative phosphorylation and cellular energy production. Although reduced complex IV activity has been observed in long-term therapy, the connection between treatment duration and mitochondrial dysfunction in humans remains insufficiently defined. METHODS: Forty patients were included and stratified by treatment duration: 2-7 days (group 1), 8-14 days (group 2) and more than 14 days (group 3). To evaluate mitochondrial function in peripheral blood mononuclear cells (PBMCs) from patients treated with linezolid for different durations, Seahorse XF was used. To assess protein expression changes associated with mitochondrial toxicity, LC-MS/MS was used. Differentially expressed proteins were identified in R based on fold-change thresholds (|log₂FC|≥0.58) and p < 0.05, and results were visualized with volcano plots and STRING interaction networks. RESULTS: All the groups were similar in terms of variables and characteristics. Mitochondrial respiration declined progressively with treatment duration and platelet counts showed a parallel reduction. Proteomic analysis identified one cluster of downregulated protein in group 2 of patients and two in group 3; they were involved in mitochondrial ATP synthesis-mainly subunits of complexes I and IV of the respiratory chain-supporting a concordant functional and molecular pattern of mitochondrial impairment. CONCLUSIONS: Prolonged linezolid treatment was associated with progressive mitochondrial dysfunction, as reflected by both functional assays and proteomic profiles. Concordant changes in respiration and protein expression support mitochondrial involvement in linezolid-related toxicity and suggest that, in addition to previously reported alterations in complex IV, complex I proteins may also be affected in treated patients.
Single-cell analysis reveals an endothelial TP53-CXCL14 axis in breast cancer progression.
Chen W, Liu X, Li S … +1 more , Chen Z
J Transl Med · 2026 Jun · PMID 42260654 · Full text
BACKGROUND: The TME of BRCA plays a core role in disease progression and treatment resistance. As a pleiotropic chemokine, CXCL14 exhibits context-dependent roles in cancer. While its potential prognostic value in BRCA h...
BACKGROUND: The TME of BRCA plays a core role in disease progression and treatment resistance. As a pleiotropic chemokine, CXCL14 exhibits context-dependent roles in cancer. While its potential prognostic value in BRCA has been noted, its precise role and regulatory mechanisms remain elusive. METHOD: The expression of CXCL14, its prognostic significance, and its association with the immune microenvironment were systematically analyzed using public databases, such as TCGA, GEO, and cBioPortal. In vitro experiments were performed to generate HUVEC cells with stable TP53 silencing or overexpression. ChIP-qPCR and dual-luciferase reporter assays were used to assess TP53's effect on CXCL14 transcriptional regulation. In vivo tumor growth was evaluated in a xenograft mouse model co-injected with HUVECs and MDA-231 cells. RESULTS: High expression of CXCL14 was significantly associated with rounding down for 4 and rounding up for 5 indicators, such as favorable OS (HR = 0.64, P = 0.006), and PFS (HR = 0.65, P = 0.002) in BRCA patients, and indicated a better response to immune checkpoint inhibitor treatment. Its expression is associated with a remodeled immune microenvironment, characterized by an increase in the infiltration of anti-tumor immune cells (e.g., CD8⁺T cells) and a decrease in immunosuppressive cells (e.g., M2 macrophages). ScRNA-seq analysis identified ECs as the main cellular source of CXCL14 in the TME for the first time. Mechanistic analyses indicated that mutant TP53 binds the CXCL14 promoter, supporting transcriptional repression. Functional experiments confirmed that the secretion of CXCL14 by TP53-mutated ECs decreased, thereby promoting the migration and invasion of BRCA cells. In vivo, co-injection of TP53-mutant (R175H) HUVECs with BRCA cells resulted in significantly larger and heavier tumors, accompanied by increased Ki-67 staining and decreased CXCL14 expression, compared to the wild-type TP53 group. CONCLUSION: Our findings indicate that CXCL14 serves as a promising independent prognostic factor associated with an anti-tumor immune microenvironment in BRCA, with ECs identified as a major source. Furthermore, TP53 mutations may promote BRCA progression by repressing endothelial through CXCL14 transcription.
Terbium-doped 3D-printed carbonate hydroxyapatite scaffold enhances bone regeneration.
Liu P, Shen J, Bian Y … +4 more , Han S, Duan X, Yuan Y, Wang Z
J Transl Med · 2026 Jun · PMID 42260646 · Full text
BACKGROUND: Oral and maxillofacial bone defects present significant clinical challenges. This study developed a 3D-printed terbium-doped carbonate hydroxyapatite scaffold to enhance bone regeneration. METHODS: The Tb-CHA...
BACKGROUND: Oral and maxillofacial bone defects present significant clinical challenges. This study developed a 3D-printed terbium-doped carbonate hydroxyapatite scaffold to enhance bone regeneration. METHODS: The Tb-CHA scaffold was fabricated via 3D printing and evaluated for its physicochemical properties, biocompatibility, biodegradability, and mechanical strength. In vitro experiments assessed the scaffold's effects on proliferation and differentiation of pre-osteoblasts (MC3T3-E1 cells), while in vivo osteogenic and angiogenic capabilities were tested using a rat calvarial defect model. RESULTS: The Tb-CHA scaffold exhibited suitable mechanical properties, biodegradability, and biocompatibility, providing an optimal microenvironment for bone regeneration. In vitro, Tb-CHA significantly enhanced MC3T3-E1 cell proliferation and osteogenic differentiation. In vivo, the scaffold promoted robust bone tissue and vasculature regeneration in rat calvarial defects, outperforming conventional materials. CONCLUSIONS: Tb-CHA represents a promising biomaterial for bone defect repair, combining the advantages of 3D printing precision and the osteogenic potential of terbium. This study pioneers the application of rare earth elements in bone tissue engineering, offering a novel strategy for clinical challenges in dentistry and orthopedics.
Meta-ERS: an exposome-based risk score using non-genetic factors to guide osteoporosis prevention.
Zheng Y, Li Y, Gao Y … +6 more , Li J, Suo C, Jiang Y, Jin L, Xu K, Chen X
J Transl Med · 2026 Jun · PMID 42260587 · Full text
BACKGROUND: Osteoporosis is influenced by both genetic and environmental factors, yet the relative contribution of the exposome remains unclear. This study aimed to systematically identify non-genetic exposures related t...
BACKGROUND: Osteoporosis is influenced by both genetic and environmental factors, yet the relative contribution of the exposome remains unclear. This study aimed to systematically identify non-genetic exposures related to osteoporosis and develop an exposome risk score (ERS) to evaluate individual osteoporosis susceptibility. METHODS: We conducted an exposome-wide analysis of 477,792 UK Biobank participants to identify key exposures associated with osteoporosis. The selected exposures were combined into a weighted Meta-ERS and validated in the Scotland/Wales cohort. The Meta-ERS was further compared with polygenic risk scores (PRS) and linked to plasma proteomics to explore underlying biological pathways. RESULTS: We identified 41 independent non-genetic exposures spanning socioeconomic status, mental health, sleep, diet, smoking, physical activity, environment, and marital status, with socioeconomic status and mental health emerging as the most significant drivers. Based on the identified exposures, we constructed eight domain-specific exposure risk scores and integrated them into a weighted Meta-ERS. The Meta-ERS (R = 5.1%; Proportion of Chi-Square = 14.3%) demonstrated an ability to explain osteoporosis variation that was on par with polygenic risk scores (R = 4.8%; Proportion of Chi-Square = 12.0%). Importantly, modifying unfavorable exposures mitigated the negative effect of PRS on osteoporosis, particularly among high PRS individuals (1.5- to 1.8-fold greater absolute risk reduction than in those with low PRS). Proteomic analyses further revealed potential mechanisms through which the exposome influences osteoporosis, including hormonal regulation, inflammation, ossification, muscle development, lipid metabolism, and accelerated bone aging. Among these, growth/differentiation factor 15 was identified as a key mediator protein, with a mediation proportion of 13.13%-36.52%. CONCLUSIONS: The Meta-ERS facilitates the quantification of individual osteoporosis risk and identifies modifiable exposures for targeted prevention. Its application can enable personalized risk stratification and guide lifestyle or environmental interventions.
Multiomic characterization of malignant pulmonary nodules and development of a methylation-based diagnostic Model.
Zhou W, Xie T, Wu Q … +8 more , Song M, Weng J, Zhang J, Gao X, Zheng M, Wang Z, Zhou Y, Li Y
J Transl Med · 2026 Jun · PMID 42260586 · Full text
BACKGROUND: The molecular distinction between benign and malignant pulmonary nodules remains a significant diagnostic challenge. While genomic drivers are well studied, multiomic integration of the epigenetic-transcripti...
BACKGROUND: The molecular distinction between benign and malignant pulmonary nodules remains a significant diagnostic challenge. While genomic drivers are well studied, multiomic integration of the epigenetic-transcriptional landscape and its translation into noninvasive tools are lacking. METHODS: We performed a multiomic characterization (genomic, epigenomic, and transcriptomic) of 158 pulmonary nodules. Unsupervised factor analysis integrated these layers to identify core regulatory axes. A 9-gene cell-free DNA (cfDNA) methylation classifier was developed and validated in blood and tissue cohorts. RESULTS: Genomic profiling revealed EGFR mutations (exclusive to malignant nodules) and MYC amplification as fundamental initiators of malignancy. Multiomic factor analysis (Factor 1) revealed profound genetic‒epigenetic synergy, in which these alterations dictate a permissive methylome, leading to aberrant epigenetic programming of chromatin accessibility, as well as epigenetic-transcriptional effects: hypomethylation at the promoters of cell cycle genes that augments their expression, and hypermethylation at immune related pathways gene loci that silences their transcription. This effect orchestrates formation of proproliferative (E2F target/G2M checkpoint) and "immune-cold" malignant phenotype, characterized by elevated Treg/CD8+ ratios and fibroblast recruitment. Notably, we observed a gradual accumulation of methylation aberrations along the premalignant-to-invasive continuum (adenocarcinoma in situ [AIS]→minimally invasive adenocarcinoma [MIA]→adenocarcinoma [ADC]), identifying progressive epigenetic dysregulation as a hallmark of tumor aggressiveness. Global methylome remodeling drives ADC progression through hypermethylation-mediated silencing of tumor suppressors (RASA3 and PPARG) and hypomethylation-activated oncogenic axes, specifically the GDF15 axis, which independently predict poor survival in patients with lung ADC in the TCGA cohort. We translated these tissue-derived insights into a 9-gene cfDNA methylation classifier, which achieved exceptional diagnostic accuracy across independent cohorts (training AUC = 1.00; test AUC = 0.93; tissue AUC = 0.96). Rooted in the biological "ground truth" of tissue dysregulation, this classifier functions specifically as a functional readout of the core cell cycle and proliferative pathways, offering a robust, noninvasive tool for the biology-informed risk assessment of pulmonary nodules. CONCLUSIONS: This study delineates an epigenetic-transcriptional regulatory network that drives nodule malignancy. Our findings provide a robust theoretical foundation and a high-performance liquid biopsy tool for the precise, noninvasive diagnosis of pulmonary nodules.
An epithelial cell fate-driven predictive model for liver metastasis risk in primary colorectal cancer through single-cell and multi-omics integration.
Yin M, Bo X, Li Y … +9 more , Yu S, Lin Z, Wang M, Wu J, Zhou M, Kong L, Zhu Y, Xiao W, Ding Y
J Transl Med · 2026 Jun · PMID 42260568 · Full text
BACKGROUND: Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide, with colorectal cancer liver metastases (CRLM) representing a principal cause of CRC-related mortality. However, a lack of molecul...
BACKGROUND: Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide, with colorectal cancer liver metastases (CRLM) representing a principal cause of CRC-related mortality. However, a lack of molecular subgroups based on the differentiation states of diverse cell types in CRLM poses a significant barrier to progress in precision therapy. METHODS: We integrated single-cell RNA sequencing (scRNA-seq, GSE178318) of paired CRLM tissues to define an epithelial cell fate gene signature. To evaluate the intrinsic "malignant seed" potential, this signature was projected onto a large-scale primary reference cohort (TCGA-COAD/READ, N = 433) using consensus clustering to establish the Malignant Development Signature of CRLM (MDSCRLM). Comprehensive multi-omics analyses-encompassing somatic mutations, copy number variations, tumor mutational burden (TMB), and ATAC-seq chromatin accessibility (N = 81)-alongside immune microenvironment deconvolutions and proteomic data integration were performed. The clinical relevance of the MDSCRLM model was externally validated using immunohistochemistry in an independent clinical cohort of 45 patients. Furthermore, the biological function of HSPA1A, a core marker, was experimentally verified through in vitro assays and in vivo metastasis models. RESULTS: The MDSCRLM system discriminates three distinctmetastatic risk trajectories: Cluster 1-Aggressive-Metastasis-Enhanced CRLM (AMECRLM), Cluster 2-Cell Cycle-Active CRLM (CCACRLM), and Cluster 3-Growth-Inhibited CRLM (GICRLM). Survival analyses in the primary reference cohort validated the biological plausibility and prognostic impact of this model, revealing that GICRLM is associated with the most favorable prognosis while AMECRLM confers the poorest outcome. Our findings delineate distinct patterns of cellular heterogeneity, genomic instability (TP53 mutations), and gene expression across CRLM developmental stages. Prognostic validation in the clinical cohort and functional validation demonstrating that HSPA1A knockout attenuates tumor invasion and metastasis robustly supported the robustness of the MDSCRLM risk stratification. CONCLUSIONS: We established a novel, clinically relevant CRLM risk stratification model with strong diagnostic and prognostic potential. By identifying pre-existing malignant features and stage-specific therapeutic vulnerabilities within the primary tumor, this model bridges the gap between biological discovery and precision medicine in advanced colorectal cancer.
SIRT3 regulates mitochondrial metabolism through deacetylation of SLC25A6 to impact gastric cancer progression and drug resistance.
Meng W, Lang C, Gan J … +9 more , Mu X, Tang L, Wang J, Liu Y, Zhu Y, Du Y, Zhang H, He Q, Liu J
J Transl Med · 2026 Jun · PMID 42260555 · Full text
BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, largely due to late diagnosis, rapid progression, and the development of chemoresistance. Mitochondrial metabolic reprogrammi...
BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, largely due to late diagnosis, rapid progression, and the development of chemoresistance. Mitochondrial metabolic reprogramming has emerged as a critical driver of tumor progression and drug resistance. Sirtuin-3 (SIRT3), a mitochondrial NAD -dependent deacetylase, plays a context-dependent role in cancer biology; however, its function and underlying mechanism in GC progression and cisplatin (DDP) resistance remain unclear. This study aimed to explore the biological role and molecular mechanism of SIRT3 in GC. MATERIALS AND METHODS: SIRT3 expression and prognostic value were analyzed using The Cancer Genome Atlas (TCGA) database and validated in human GC tissues by qRT-PCR, Western blotting, and immunohistochemistry. Knockdown and overexpression models of SIRT3 were established in AGS and HGC27 GC cell lines. Cell proliferation, migration, invasion, and apoptosis were assessed using CCK-8, colony formation, Transwell, wound-healing, and flow cytometry assays. Cisplatin-resistant GC cell lines and nude mouse xenograft models were established to evaluate chemosensitivity in vitro and in vivo. Transcriptome sequencing (RNA-seq), co-immunoprecipitation, acetylation assays, and cycloheximide chase assays were performed to identify downstream or upstream targets and mechanisms of SIRT3. Rescue experiments were conducted to confirm the dependency of SIRT3 and differentially expressed genes. RESULTS: SIRT3 expression was significantly upregulated in GC tissues and was associated with poor overall survival. SIRT3 knockdown markedly inhibited GC cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and tumorigenesis, while promoting apoptosis both in vitro and in vivo. Conversely, SIRT3 overexpression enhanced malignant phenotypes. SIRT3 was significantly overexpressed in cisplatin-resistant GC tissues and cell lines, and its upregulation conferred resistance to DDP, whereas SIRT3 silencing sensitized GC cells to DDP in vitro and in xenograft models. RNA-seq identified SLC25A6 as a key downstream target of SIRT3. Mechanistically, SIRT3 directly interacted with SLC25A6 (ANT3/AAC3) and reduced its acetylation level, thereby enhancing its protein stability. SLC25A6 silencing phenocopied the effects of SIRT3 knockdown, and rescue experiments confirmed that the oncogenic and chemoresistant functions of SIRT3 were dependent on ANT3. CONCLUSION: SIRT3 promotes GC progression and chemoresistance by deacetylating and stabilizing the mitochondrial ADP/ATP translocator SLC25A6 (ANT3), thereby enhancing mitochondrial metabolic activity. The SIRT3-ANT3 axis represents a novel molecular mechanism driving GC malignancy and chemoresistance and may serve as a promising therapeutic target for improving treatment efficacy in GC.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe