The pathological hypercoagulable state and associated risk of thrombosis in colorectal cancer (CRC) persist throughout the disease course. Accurate identification of patients at high risk of venous thromboembolism (VTE) and judiciously applying drug or mechanical prevention measures can significantly reduce the incidence of VTE. The review details a range of biomarkers, including platelet count, soluble P-selectin, D-dimer, and vascular endothelial growth factor (VEGF), which have been shown to correlate with increased VTE risk in CRC patients. In addition to the biomarker analysis, the review makes important recommendations for the routine monitoring of these biomarkers in CRC patients, especially those at higher risk for VTE. Furthermore, it discusses the integration of these biomarkers into clinical VTE risk prediction models, advocating for personalized and targeted thromboprophylaxis strategies. The review also explores future research directions, emphasizing the potential of antiplatelet and anticoagulant therapies in improving the prognosis of CRC patients by reducing thromboembolic events. This narrative review not only deepens our understanding of the molecular mechanisms driving cancer-associated thrombosis but also paves the way for novel therapeutic interventions aimed at preventing VTE in CRC patients.

Herein, we report a rationally designed dual-mode lateral flow assay (LFA) biosensor for the visual detection of microRNA-21 (miRNA-21), a critical breast cancer biomarker. The platform utilizes a synergistic readout of colorimetric signals from gold nanoparticles (AuNPs) and fluorescent signals from quantum dot nanobeads (QDNBs). Upon the specific introduction of target miRNA-21, the conformation of optimized hairpin nucleic acid probes conjugated on the nanomaterials is disrupted. This structural transition exposes capture sites, generating an AuNP-mediated colorimetric signal and a restored QDNBs fluorescence signal on the test lines by mitigating the inner filter effect (IFE) between them. Compared with conventional single-signal or amplification-dependent miRNA sensors, the proposed LFA integrates amplification-free target recognition, complementary AuNP-based colorimetric and QDNB-based fluorescent readouts, and IFE-regulated fluorescence recovery on a single strip, enabling visual screening and smartphone-assisted semi-quantitative analysis without complex instrumentation. Under optimal conditions, both the colorimetric and fluorescent readouts display broad linear correlations with miRNA-21 concentrations (5-1000 nM and 2.5-1000 nM, respectively), the limits of detection (LOD) of 1.599 nM and 1.354 nM. Furthermore, the platform demonstrates remarkable specificity against homologous miRNAs and robust stability. In spiked human serum, the assay achieves satisfactory recovery rates (91.8%-113.2%) with relative standard deviations (RSDs) below 6.0%. Furthermore, a preliminary evaluation using serum samples from five breast cancer patients and five healthy individuals showed clearly distinguishable colorimetric and fluorescent responses between the two groups, supporting the effectiveness of the proposed probe for miRNA-21 detection in real serum samples. These results indicate the potential of the dual-signal LFA platform for further clinical application.

Platelet dysfunction drives bleeding complications in patients with advanced chronic kidney disease (CKD), worsening clinical outcomes. However, the underlying mechanisms remain unclear, limiting treatment options. In this study, we identified the expression of urea transporter B (SLC14A1/UT-B) in human and mouse platelets. By analyzing a clinical cohort of patients with CKD, we demonstrated that single-nucleotide polymorphisms in SLC14A1 were associated with bleeding events in CKD. Using a 5/6 nephrectomy (5/6 Nx) mouse model and blood samples from patients with advanced CKD, we found that SLC14A1/UT-B-mediated urea influx underlies platelet dysfunction in advanced CKD given that both genetic knockout of Slc14a1 or pharmacological inhibition of UT-B reversed mouse and human platelet dysfunction induced by urea or advanced CKD plasma. SLC14A1/UT-B-mediated urea influx induced protein carbamylation, which drove platelet dysfunction. By characterizing the carbamylation profiles of proteins in human and mouse platelets, we demonstrated that carbamylation disrupted cytoskeletal rearrangement, degranulation, and inside-out integrin αIIbβ3 signaling transduction during platelet activation, leading to impaired platelet aggregation, secretion, and spreading in advanced CKD. Furthermore, treatment of 5/6 Nx mice with the UT-B inhibitor PU-48 effectively preserved platelet function and improved hemostatic ability. These findings suggest that SLC14A1/UT-B promoted urea uptake in platelets and mediated bleeding in advanced CKD, highlighting its potential as a therapeutic target for managing bleeding complications in patients with advanced CKD.

Against the backdrop of a rapidly aging global population, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's continues to rise, imposing a severe socioeconomic burden. Neuroinflammation is recognized as the core mechanism linking physiological brain aging to pathological cognitive decline. This paper aims to systematically elucidate the multi-level activation mechanisms of neuroinflammation during aging and comprehensively evaluate drug intervention strategies targeting this process. Research reveals that the chronicity of neuroinflammation is driven by multiple cellular and molecular events. At the cellular level, aging and dysfunction in microglia and astrocytes lead to their respective transitions toward pro-inflammatory M1 and neurotoxic A1 phenotypes. These changes interact synergistically with blood-brain barrier dysfunction, peripheral immune cell infiltration, and abnormal aggregation of pathological proteins like Aβ and α-synuclein, forming a vicious cycle. At the molecular level, signaling pathways including NLRP3 inflammasome, NF-κB, and JAK/STAT are persistently activated, while epigenetic modifications play crucial regulatory roles. Addressing these mechanisms, this review systematically examines six major intervention strategies: modulating neuroimmune cell function, inhibiting core inflammatory pathways, targeting inflammatory mediators like cytokines, employing senolytics to clear senescent cells, enhancing endogenous anti-inflammatory defenses, and exploring multi-target natural products and drug repurposing. Research indicates that targeting neuroinflammation offers a highly promising new avenue for delaying brain aging and related diseases. However, this field still faces numerous challenges, including target specificity, blood-brain barrier delivery, individual heterogeneity, and difficulties in clinical translation. Future breakthroughs will depend on more precise drug design, innovative delivery technologies, biomarker development, and interdisciplinary collaborative research.

Abstract Liver sinusoidal endothelial cells (LSECs) form a specialized discontinuous microvascular interface between sinusoidal blood and the hepatic parenchyma. Functioning as a central regulator of hepatic homeostasis, LSECs integrate metabolic, inflammatory, and hemodynamic signals to maintain sinusoidal permeability, immune tolerance, vascular tone, and lipid exchange. During acute injury or sustained hepatic stress, LSECs may lose their differentiated sinusoidal phenotype and acquire features of capillarization, including fenestrae loss, subendothelial matrix accumulation, impaired scavenging activity, and attenuation of KLF2-eNOS-NO signaling. Capillarized LSECs are not merely a byproduct of hepatic damage; instead, they may function as early endothelial sentinels and important contributors to the amplification of parenchymal injury, inflammation, fibrogenesis, and tumor immune evasion. This review summarizes the physiological functions of LSECs and examines mechanisms through which LSEC dysfunction contributes to acute liver injury, metabolic dysfunction-associated steatotic liver disease, viral hepatitis, cirrhosis, and hepatocellular carcinoma. By comparing conserved mechanisms with disease-specific spatial and molecular triggers, this review highlights how LSEC phenotypic switching disrupts the angiocrine–immune–fibrotic axis and contributes to disease progression. Recent advances in single-cell and spatial omics, LSEC subpopulation heterogeneity, and capillarization-aware therapeutic delivery are further discussed. Finally, therapeutic reprogramming of dysfunctional LSECs toward a quiescent, fenestrated, and tolerogenic phenotype is proposed as a strategy to restore sinusoidal homeostasis and improve treatment of liver diseases.

This letter highlights emerging immune-targeted therapies for immune thrombocytopenia (ITP) presented at the 2025 ASH Annual Meeting. We summarize pivotal data, including the Phase III VAYHIT2 trial of Ianalumab, alongside novel early-phase agents targeting BAFF-R, CD38, CD19, PI3K, and cellular therapies (CD19/BCMA CAR-T), which provide crucial biological insights and hypothesis-generating signals for future ITP management.

This study aimed to explore the efficacy and safety of remimazolam vs. propofol for sedation during video laryngoscopy in cervical spondylosis patients with suspected difficult laryngoscopy. In this single-center, prospective, randomized controlled study, 85 patients with Modified Mallampati class III or IV and limited cervical spine mobility were recruited and randomly assigned (1:1 ratio) to receive either remimazolam or propofol sedation. The primary outcome was the incidence of hypoxemia (SpO₂< 90

Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes in a wide range of cancers but may also induce hematological toxicities and thrombosis risk. This study comprehensively evaluated hematological and thrombotic adverse events (AEs) associated with ICIs in real-world settings using the FDA Adverse Event Reporting System (FAERS) database, aiming to characterize their clinical features. Data were extracted from the FAERS database (Q1 2014 to Q4 2024) for disproportionality analysis. AEs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). Associations between ICIs and hematological/thrombotic AEs were assessed via the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) methods. Clinical characteristics of affected patients were analyzed, and time-to-onset across ICI regimens was further evaluated. We identified 14,753 ICI-associated hematological toxicities and thrombotic events. Among reports with available sex information, a higher reporting frequency was observed in men (50.90

Metabolic syndrome describes a set of risk factors that can eventually lead to the occurrence of cardiovascular and cerebrovascular disease. Metabolic syndrome has emerged as a significant global health issue, associated with various metabolic diseases, including obesity, diabetes, hypertension, dyslipidemia, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, and other metabolic disorders. Here, we summarize the intricate mechanisms including insulin resistance, chronic low-grade inflammation, oxidative stress, and epigenetic modifications, and how they contribute to the disease progression of metabolic syndrome. The gut-adipose tissue axis in the progression of metabolic syndrome is emphasized here, mainly involving adipocyte-derived extracellular vesicles and adipokines, as well as specific gut microbiota and their secreted factors, such as lipopolysaccharide, short-chain fatty acids, endocannabinoids, bile acids, aryl hydrocarbon receptor ligands, and tryptophan derivatives. Furthermore, the contemporary management for metabolic syndrome mainly includes some established pharmacological treatments such as GLP-1 receptor agonists, SGLT2 inhibitors, and RAAS inhibitors, as well as promising emerging therapies targeting the gut-adipose tissue axis such as lifestyle modifications, prebiotics, probiotics, synbiotic supplements, FMT, bariatric surgery, CB1R antagonists, and novel pharmacological agents. These strategies may pave the way for the development of effective treatments for metabolic diseases in future research.

This study aimed to provide a comprehensive review of adverse events (AEs) associated with factor Xa (FXa) inhibitors in pediatric patients. We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and the European Union Clinical Trials Register for English-language records from the establishment of the database up to October 17, 2023. Both randomized controlled trials and single-arm trials were included. AEs were analyzed using a Bayesian hierarchical model. For the pharmacovigilance study, data from the US Food and Drug Administration Adverse Event Reporting System from January 1, 2007, to December 31, 2023, were obtained. The proportional imbalance method and the Medicines and Healthcare products Regulatory Agency method were used to detect AE signals. Further characterization of patients presenting with AEs was performed. Of 451 records identified, 12 eligible studies were included. A total of 50.6

Abstract Background Epigenetic modifications have been proved to play important roles in the spinal degenerative diseases. As a type of noncoding RNA, the microRNA (miRNA) is a vital class of regulatory factor in the epigenetic modifications, while the role of miRNAs in the regulation of epigenetic modifications in ligamentum flavum hypertrophy (LFH) has not been fully investigated. Methods The miRNA sequencing analysis was used to explore the change of miRNA expression during the fibrosis of ligamentum flavum (LF) cells caused by the TGF-β1 (10 ng/ml). The downregulated miRNA miR-335-3p was selected to investigate its effects on the fibrosis of LF cells and explored the accurate relevant mechanisms. Results A total of 21 miRNAs were differently expressed during the fibrosis of LF cells. The downregulated miR-335-3p was selected for further investigation. MiR-335-3p was distinctly downregulated in the LFH tissues compared to non-LFH tissues. Overexpression of miR-335-3p could inhibit the fibrosis of LF cells. Further research showed miR-335-3p prevented the fibrosis of LF cells via binding to the 3′-UTR of SERPINE2 to reduce the expression of SERPINE2. The increased SERPINE2 expression might promote the fibrosis of LF cells via the activation of β-catenin signaling pathway to promote the transcription of fibrosis-related genes (ACTA2 and COL3A1). Conclusions Our results revealed that miR-335-3p prevented the fibrosis of LF cells via the epigenetic regulation of SERPINE2/β-catenin signaling pathway. The epigenetic regulator miR-335-3p might be a promising potential target for the treatment of LFH. Graphical Abstract

Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which places heavy burdens on society and individuals. Surgical intervention is the conventional therapy for IDD, but patients who undergo surgery face relatively high risks of recurrence and complications. Therefore, a relatively less invasive and efficient treatment for IDD is urgently needed. In this study, we constructed a novel nanobiomaterial, named Hi-Exos, to slow IDD. Hi-Exos are exosomes derived from mesenchymal stem cells exposed to hypoxic and inflammatory environments. Hi-Exos could relieve the senescence of nucleus pulposus cells and slow IDD through an epigenetic modification mechanism by introducing the epigenetic factor miR-221-3p into senescent nucleus pulposus cells to reduce DDIT4 expression and inhibit the activation of NF-κB signalling pathway. This study provided a novel strategy for IDD treatment involving the use of Hi-Exos to deliver miR-221-3p to reduce the senescence of nucleus pulposus cells and repair IDD via epigenetic modifications.

AIMS:Coagulation factor XI (FXI) plays a crucial role in the intrinsic coagulation pathway, and inhibitors targeting it may mitigate the risk of haemorrhage compared to anticoagulants currently on the market. SKB336, a novel selective inhibitor of FXI/FXIa, has been shown to prolong the activated partial thromboplastin time (APTT) in both in vitro and in vivo studies. This study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of SKB336 in healthy subjects. METHODS:In this randomized, single-blinded, placebo-controlled and dose-escalation first-in-human phase I study, 60 healthy subjects were allocated to 6 cohorts (0.1, 0.3, 0.6, 1.25, 2.5 and 4 mg/kg) and received a single subcutaneous injection of SKB336 or placebo in a 4:1 ratio. The safety, tolerability, pharmacokinetics and immunogenicity were measured up to 85 days postdose. Exploratory analysis consisted of FXI activity and APTT. RESULTS:SKB336 was well tolerated in all 6 cohorts, without any haemorrhagic events, reported deaths or serious adverse events. No significant dose-dependent correlation was observed with the incidence of adverse events. Dose-dependent increases in the maximum observed drug concentration and area under the plasma concentration-time curve were observed. The mean elimination half-life was 21.3-33.5 days, indicating a potential monthly dosing frequency. The maximum inhibition rate of FXI activity for all 6 cohorts reached 0, 17, 28, 48, 54 and 59%, respectively. The maximum APTT ratio to baseline reached 1.09-, 1.26-, 1.47-, 1.77, 1.91- and 2.00-fold, respectively. CONCLUSION:SKB336 was generally tolerated, without any bleeding events in healthy volunteers. Besides, SKB336 presented a persistent dose-dependent prolongation of APTT and duration of FXI inhibition.

Intervertebral disc degeneration (IDD) is a leading cause of discogenic lower back pain, yet the crosstalk between macrophage polarization and nucleus pulposus (NP) cell senescence in IDD progression remains poorly understood. Emerging therapies using human induced pluripotent stem cell (iPSCs)-derived mesenchymal stem cells (iMSCs) show promise for IDD treatment. In this study, it is first demonstrated that senescent NP cells promote macrophage polarization toward the pro-inflammatory M1 phenotype in coculture systems. Reciprocally, conditioned medium from M1 macrophages exposed to senescent NP cells accelerates senescence in healthy NP cells. Notably, it is identified that iMSCs-derived exosomes break this pathogenic cycle by reprogramming M1 macrophages toward anti-inflammatory M2 phenotypes. Mechanistically, these exosomes deliver miR-100-5p to suppress mTORC1 signaling and regulate glycolysis metabolic reprogramming in macrophages. These findings are corroborated in a rat IDD model, where iMSC-exosomes mitigate IDD progression in vivo. This work elucidates a novel iMSC-exosomes mediated mechanism regulating macrophage-NP cell interactions, which provides a promising therapeutic strategy for IDD intervention.

Hepatocellular carcinoma (HCC) and breast cancer (BC) are diseases with high incidence rates and mortality. The detection of tumor biomarkers in serum has significant implications for improving the early detection efficiency of cancer. However, the indicative significance of individual tumor markers can vary, leading to the need for simultaneous evaluation of two or more cancer markers to enhance diagnostic efficiency. This study selected three fluorescent nanomaterials to label nucleic acid aptamers (Apt) and introduced hybrid chain reaction (HCR) to amplify the detection signals, constructing a single-excitation three-emission fluorescent probe for the high-sensitivity simultaneous detection of PTK7, GPC3 and MUC1. This probe demonstrates satisfactory performance both in detecting any single target and in simultaneously detecting all three targets. The sensitivity of the probe is high, with a limit of detection (LOD) of 6 pM for PTK7, 53 pM for GPC3, and 29 pM for MUC1. After methodological validation, the probe was employed to simultaneously measure PTK7, GPC3, and MUC1 in the serum of healthy individuals, HCC patients, and BC patients, confirming that these three biomarkers can be utilized for tumor diagnosis. Furthermore, the probe was successfully applied for multi-targets co-localization in-situ imaging of tumor cells and normal cells, validating its capacity for in-situ cellular imaging diagnosis. This research provides a foundation for early diagnosis of HCC and BC and offers a template for seeking appropriate combined detection of multiple tumor biomarkers. By modifying the Apt, more optimal biomarkers can be identified, showcasing the great potential for assisting clinical diagnosis.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by dysregulated differentiation and uncontrolled proliferation of myeloid precursor cells. AML is the second most common type of leukemia after acute lymphoblastic leukemia, yet it has the lower survival rates, with only approximately 30% of adult patients surviving five years post-diagnosis. Standard treatment regimens typically include intensive chemotherapy, advances in allogeneic hematopoietic stem cell transplantation (allo-HSCT) have significantly improved outcomes in the treatment of AML. Advances in molecular profiling technologies have significantly enhanced our understanding of the genetic and epigenetic alterations that drive AML, revealing numerous novel therapeutic targets. Consequently, targeted molecular therapies and epigenetic treatments are becoming increasingly important. Moreover, immunotherapy represents a promising therapeutic strategy that has demonstrated considerable potential in the context of AML. This review summarizes new strategies and emerging therapeutic targets in AML, with a particular focus on recent advancements in immunotherapy. It also explores the feasibility of integrating these therapeutic approaches into current treatment paradigms and their potential impact on future clinical practices.

Regular monitoring of serum antibody levels is crucial for preventing interference with therapeutic effectiveness and reducing the risk of toxicity. To address this, a CRISPR/Cas12a sensing system with circular CRISPR RNAs (CcrRNAs) is described for highly sensitive detection of anti-digoxin (Anti-Dig) antibodies in human serum. In this work, the topology structure of CcrRNAs effectively suppresses the function of linear crRNAs (LcrRNAs), making them unable to regulate the cis-/trans-cleavage activity of the Cas12a system. Therefore, a low-background is obtained in the absence of targets. The target Anti-Dig antibodies trigger the assembly of the complete multicomponent nucleic acid enzyme (MNAzyme) with active enzyme activity, which can transform CcrRNAs into LcrRNAs. The LcrRNAs further recover the trans-cleavage activity of the CRISPR/Cas12a system, which can degrade single-stranded reporter DNA to generate a significantly enhanced fluorescent signal. This method enables sensitive detection of Anti-Dig antibodies as low as 15 pM within 60 min and exhibits a linear detection range of 25 pM-50 nM. It also exhibits excellent selectivity against non-target antibodies and has been successfully validated in diluted serum samples, achieving a recovery rate ranging from 96.16 % to 103.08 %. This novel CRISPR/Cas12a sensing system with CcrRNA represents a powerful and efficient tool for detecting low-abundance biomarkers in complex biological samples.

Modified new drugs are pivotal in advancing innovative therapies through repurposing existing therapeutic agents. The regulatory framework, including the pertinent regulations and policies, plays a crucial role in shaping the development and evolution of these drugs. This retrospective study systematically compared the regulatory approvals of modified new drugs via the 505(b)(2) new drug application (NDA) pathway in the United States (US) and Class 2 NDA pathway in China from 2017 to 2023, which focused on distinctions in registration classifications, availability, therapeutic indications, dosage forms, modifications, clinical advantages and clinical study designs. The findings indicate that the US has more detailed and comprehensive classification systems, as well as a higher number of approvals (417 vs. 99). Moreover, the modified new drugs approved in China still exhibit significant gaps in indication distribution, dosage forms, and modifications compared to those in the US. Notably, a greater proportion of confirmatory clinical studies were conducted for Class 2 NDAs (81.4 %) than 505(b)(2) NDAs (41.0 %), with a significant difference in the use of active controls (48.6 % in China vs. 26.4 % in the US, P = 0.002). Additionally, the combination of emerging technologies in modified new drugs presents both technical and regulatory challenges for authorities. It raises worthwhile questions about how regulators will evaluate medical products developed with entirely new technologies. Therefore, it is recommended that Chinese regulators refine registration classifications, reassess the positioning of modified new drugs, and expand the definition of clinical advantage within the policy and regulatory framework. These measures are essential for addressing unmet medical needs and fostering a conducive ecosystem for the advancement of modified new drugs.