Blood Center of Zhejiang Province

N6-methyladenosine (m6A) is a chemical modification of adenosine in RNA that plays a crucial role in the regulation of gene expression. As the most abundant form of RNA chemical methylation, m6A is aberrantly expressed in hepatocellular carcinoma (HCC), where it affects multiple biological processes including targeted RNA splicing, transport, degradation, stabilization, and translation. RBM15B (RNA-binding motif protein 15B), is a gene that encodes a protein involved in RNA processing and regulation. RBM15B is a member of the RNA-binding motif (RBM) protein family, which plays diverse roles in post-transcriptional gene regulation. RBM15B is proven to be involved in mRNA processing, including pre-mRNA splicing, mRNA transport, and mRNA stability. It may also participate in other RNA-related processes such as mRNA translation and RNA decay. We investigated the phenotypes of RBM15B in HCC using the TCGA database, in-vitro, and in vivo assays. m6A dot blot was used to assess RNA methylation levels and Merip-seq/RNA-seq were employed to explore the biological effects and potential mechanisms of RBM15B in HCC. We hypothesized that RBM15B may regulate ITSN2 expression in HCC. To test this, RNA immunoprecipitation (RIP) followed by qRT-PCR was applied for the identification and characterization of target ITSN2 mRNA that interacted with RNA binding protein IGF2BP1, which may mediate the effects of RBM15B. To further elucidate the functional relationship between RBM15B and ITSN2, we performed rescue assays of cell proliferation and migration to determine whether RBM15B over-expression is able to restore the loss of function induced by ITSN2 knockdown to an extent. High levels of RBM15B were verified by both TCGA data and our cohort. High levels of RBM15B predicted a poor prognosis. RBM15B promotes HCC propagation and invasion in vitro and in vivo. RBM15B regulates the m6A of intersectin2 (ITSN2) mRNA via insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1)-facilitated stabilization of ITSN2 mRNA. ITSN2 depletion rescued the tumor-promoting phenotype induced by RBM15B overexpression. In summary, RBM15B-regulated m6A in ITSN2 mRNA facilitates HCC progression via IGF2BP1-guided stabilization of ITSN2 mRNA. Our study illustrates the importance of the RBM15B-IGF2BP1-ITSN2 regulatory axis based on m6A activity and provides new insights into epi-transcriptomic maladjustments of initiation and metastasis in HCC.

Nifuroxazide (NFX), an antibacterial agent, also exhibits notable antitumor effects by inhibiting STAT3 signaling, which is often aberrantly activated and linked to chemoresistance in tumors such as hepatocellular carcinoma (HCC). Combining NFX with chemotherapy may enhance therapeutic efficacy, but its poor solubility limits oral bioavailability. To address this, we developed a biomimetic delivery system by loading NFX into murine macrophage-like RAW264.7 cells (Mφ-NFX). This strategy aims to improve drug delivery, enhance antitumor effects, with the potential to circumvent or overcome drug resistance. We evaluated the efficacy of Mφ-NFX alone and in combination with Oxaliplatin in vitro and in preclinical HCC models. Macrophages effectively carried and delivered NFX to tumor cells and tissues without significant toxicity to the carriers. Additionally, NFX promoted macrophage polarization toward the M1 phenotype within the tumor microenvironment. Mφ-NFX significantly inhibited tumor growth and increased the M1/M2 macrophage ratio. Co-treatment with Mφ-NFX and Oxaliplatin demonstrated enhanced tumor suppression and modulation of the tumor microenvironment. Mechanistically, NFX and Oxaliplatin acted synergistically via inhibition of the AKT/β-catenin pathway. In conclusion, this macrophage-based NFX delivery platform offers improved antitumor activity and sensitization to chemotherapy, presenting a promising strategy for HCC treatment.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12951-026-04196-6.

While conventional large bone defect healing is a complicated process with multiple physiological limitations, our approach leverages hematoma's innate regenerative capabilities-particularly its structure and biological functions, inculding multi-functional regulation response, activating cell autophagy, resisting persistent inflammation and enhancing angiogenesis/osteogenesis eventually, which supports a new strategy to bone repair solutions. This biomimetic strategy is more compatible with the process of bone regeneration, thereby shifting the implant paradigm from passive structural support to active biological regulation. Inspired by the balloon structure, we developed microfluidic biomimetic hematoma microspheres featuring: pH-responsive GelMA outer layer and NaHS-loaded liposomal core. This dual-component system spatiotemporally releases H2S in acidic bone defects, simultaneously decreasing chronic inflammation, promoting angiogenesis, activating autophagy and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSC). ‌This biomimetic strategy recapitulates key hematoma-mediated osteogenic processes, where controlled H2S release orchestrates the interplay of angiogenesis, inflammation resolution, cell autophagy and osteogenesis.

Background and PurposeThe laparoscopic-endoscopic rendezvous procedure, which integrates laparoscopic cholecystectomy with intraoperative endoscopic retrograde cholangiopancreatography (ERCP), is an established therapeutic strategy for patients with cholelithiasis and concomitant choledocholithiasis. This study evaluated the impact of ureteral catheter-assisted antegrade guidewire intubation on the procedural success rate and duration of the rendezvous technique, with additional assessment of safety and clinical efficacy.MethodsClinical data were retrospectively analyzed from patients with cholelithiasis and concomitant choledocholithiasis who underwent laparoscopic cholecystectomy at the South Campus of Taizhou Hospital (Enze Hospital), Zhejiang Province, between May 2019 and December 2022. A total of 116 patients were assigned to either a control group or an intervention group in which ureteral catheter-assisted guidewire insertion was employed.ResultsThe success rate of antegrade guidewire intubation was 98.3% in the intervention group, compared to 91.2% in the control group. The intervention group demonstrated a statistically significant reduction in guidewire insertion time (p < 0.05). No statistically significant differences were observed between groups in terms of intraoperative hospitalization costs, total hospitalization duration, postoperative serum amylase levels or postoperative hospitalization duration (p > 0.05). The total operative duration tended to be lower but did not reach statistical significance in the intervention group compared to the control group, with a p-value of 0.054. No cases of postoperative bile leakage were reported. In the control group, the incidence of acute pancreatitis was 2%, and the incidence of hyperamylasemia was 28.8%. In the intervention group, hyperamylasemia occurred in 25.9% of cases, with no reported instances of acute pancreatitis. Additionally, one patient in the control group developed a pulmonary embolism, and two patients developed ascites accompanied by fever.ConclusionThe use of ureteral catheter-assisted antegrade guidewire intubation during the laparoscopic-endoscopic rendezvous procedure appears to be a safe and clinically effective approach for managing cholelithiasis and concomitant choledocholithiasis. This technique is associated with a high success rate of guidewire realignment, reduced procedural duration, and a lower incidence of procedure-related complications.

Methamphetamine dependence poses a significant global health challenge, yet its assessment and the evaluation of treatments like repetitive transcranial magnetic stimulation (rTMS) frequently depend on subjective self-reports, which may introduce uncertainties. While objective neuroimaging modalities such as electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) offer alternatives, their individual limitations and the reliance on conventional, often hand-crafted, feature extraction can compromise the reliability of derived biomarkers. To overcome these limitations, we propose NeuroCLIP, a novel deep learning framework integrating simultaneously recorded EEG and fNIRS data through a progressive learning strategy. This approach offers a robust and trustworthy data-driven biomarker for methamphetamine addiction. Validation experiments show that NeuroCLIP significantly improves discriminative capabilities among the methamphetamine-dependent individuals and healthy controls compared to models using either EEG or only fNIRS alone. Furthermore, the proposed framework facilitates objective, brain-based evaluation of rTMS treatment efficacy, demonstrating measurable shifts in neural patterns towards healthy control profiles after treatment. Critically, we establish the trustworthiness of the multimodal data-driven biomarker by showing its strong correlation with psychometrically validated craving scores. These findings suggest that biomarker derived from EEG-fNIRS data via NeuroCLIP offers enhanced robustness and reliability over single-modality approaches, providing a valuable tool for addiction neuroscience research and potentially improving clinical assessments.

Pocket hematoma is a common complication following cardiac implantable electronic device (CIED) implantation, traditionally perceived as a manageable local issue. Accumulating evidence, however, indicates that clinically significant pocket hematoma (CSH) is strongly associated with increased infection rates, elevated healthcare costs, and heightened mortality. Key risk factors include advanced age, low body mass index (BMI), chronic kidney disease, complex procedures (device upgrades/replacements) and periprocedural antithrombotic management, particularly uninterrupted dual antiplatelet therapy (DAPT) and heparin/low-molecular-weight heparin (LMWH) bridging strategies, which significantly elevate bleeding risk compared to continued vitamin K antagonist (VKA) therapy or direct oral anticoagulant (DOAC) protocols. Novel compression devices and topical hemostatic agents show promise for prevention, while standardized definitions and risk stratification tools are urgently needed. This review synthesizes current evidence on multifactorial pathogenesis, adverse outcomes, and evolving preventive strategies for pocket hematoma, emphasizing its underappreciated clinical significance and the critical need for optimized periprocedural management in high-risk patients.

Colorectal cancer (CRC) ranks as a leading cause of cancer-related mortality worldwide, yet its molecular mechanisms remain incompletely understood. The transcription factor LBX2 regulates morphogenesis of multiple organ systems in vertebrates, yet its role in CRC progression remains poorly understood. In the study, we found that LBX2 knockdown suppresses CRC proliferation in vitro and in vivo. ChIP-seq/RNA-seq identifies GFPT2 as a direct transcriptional target of LBX2. The LBX2/GFPT2 axis elevates UDP-GlcNAc levels and O-GlcNAcylation, promoting Raptor T700 glycosylation. This modification enhances mTORC1 activation by strengthening Raptor-Rag interactions, accelerating glycolysis and lactate production. Accumulated lactate induces histone H4K12 lactylation, which further upregulates LBX2 transcription, forming a positive feedback loop. Clinically, high LBX2 expression correlates with elevated PET-CT SUVmax values (indicating hyperglycolysis) in CRC patients. Patient-derived organoids with high LBX2 show increased sensitivity to the GLUT1 inhibitor. LBX2 thus serves as both a metabolic driver and a potential biomarker for CRC-targeted therapies.

Runoff forecasting is essential for flood control, disaster mitigation, and sustainable water resources management. However, runoff processes are highly nonlinear and uncertain due to multiple interacting meteorological and underlying surface factors. Current models can be divided into process-driven and data-driven types. The former offers clear physical interpretability but involves complex calibration and simplifications, while the latter captures nonlinear relationships effectively but lacks physical consistency. To integrate their strengths, this study constructs process-based models and data-driven models, and proposes two hybrid strategies: (1) incorporating intermediate variables from physical models, such as soil moisture and runoff yield, as additional features for data-driven models, and (2) embedding physics-based constraints and synthetic data into loss functions. Using the Songxi River Basin as a case study, results show that both hybrid strategies significantly outperform standalone models. SHapley Additive exPlanations (SHAP)-based interpretability analysis further reveals the contribution mechanisms of key physical variables. This study demonstrates that coupling physical processes with data-driven learning effectively enhances runoff forecasting accuracy and offers a promising paradigm to support sustainable watershed management, climate-resilient water regulation, and flood risk reduction.

Azocyclotin (ACT), a widely used organotin pesticide, poses environmental and health risks due to its endocrine-disrupting effects. While prior studies linked ACT to transgenerational endocrine disruption in zebrafish via DNA methylation, the underlying molecular mechanisms remained unclear. Using zebrafish ZF4 cells as an in vitro model, we elucidated the mechanism by which ACT modulates DNA methylation. ACT exposure induced a 38.03% decrease in global DNA methylation, as determined by 5-mC quantification. Integrated whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) analyses revealed that ACT dysregulated the expression of methylation-related genes, which was subsequently verified at the protein level by Western blotting. These multiomics analyses indicated that ACT disrupts the CDK4/pRb/E2F1/DNMT1 signaling axis and revealed methylation-expression coupling in endocrine-related and imprinted genes. Co-immunoprecipitation and pull-down assays demonstrated that ACT interferes with the formation of the E2F1-DNMT1-Rb-HDAC1 complex. Furthermore, molecular docking and surface plasmon resonance assays confirmed direct binding of ACT to cyclin-dependent kinase 4 (CDK4), a finding validated using CDK4-overexpressing cell lines. These findings establish CDK4 as the primary molecular target mediating ACT's epigenetic effects. This discovery provides crucial mechanistic insights into the toxicity of ACT in aquatic organisms and its potential environmental risks.

Rapid screening of personalized drugs based on patients’ primary cell samples can provide precise and timely treatment guidance for clinical oncology patients. However, this goal faces great challenges due to the scarce clinical samples and large sample consumption, and long experimental time required by current drug screening methods. Here, a rapid, high‐throughput microfluidic drug sensitivity testing system capable of accomplishing single and combination drug screening of multiple antitumor drugs in 5 days is established with minimal amounts of clinical primary tumor samples, avoiding the need for cell pre‐expansion and preserving the tumor heterogeneity. An airflow‐impacting approach is developed to fabricate nanoliter‐scale microcavity arrays with ultra‐smooth microcavity surfaces, with which rapid formation and 3D culture of tumor cell spheroids from small numbers of cell samples, as well as the subsequent high‐throughput drug sensitivity testing can be achieved within 5 days. This applies the system in rapid drug sensitivity testing on primary samples from 21 clinical breast cancer patients to quantify the responses of patient‐derived cells to chemotherapy and endocrine drugs under both the mono‐drug and combinational‐drug treatment modes.