[摘 要] 目的：探究长链非编码RNA（lncRNA）小核仁RNA宿主基因14（SNHG14）靶向miR-579-3p/富含半胱氨酸的酸性分泌蛋白（SPARC）对肝细胞癌（HCC）细胞恶性生物学行为的影响。方法：常规培养人正常肝细胞（LO2）和HCC细胞Huh7、Hep3B、HepG2，将Huh7细胞随机分为对照组、sh-NC组、sh-SNHG14组、sh-SNHG14 + anti-NC组和sh-SNHG14 + anti-miR-579-3p组，qPCR法检测细胞中SNHG14、miR-579-3p和SPARC mRNA的表达水平，双萤光素酶报告基因实验验证SNHG14与miR-579-3p及miR-579-3p与SPARC调控关系，MTT法、划痕愈合实验、Transwell实验、流式细胞术，以及WB法分别检测各组Huh7细胞的增殖、迁移、侵袭能力、凋亡，以及Huh7细胞中PCNA、E-cadherin、vimentin、SPARC蛋白的表达。结果：在HCC细胞中SNHG14、SPARC mRNA呈高表达、miR-579-3p呈低表达（均P < 0.05）；SNHG14与miR-579-3p和miR-579-3p与SPARC mRNA间存在直接结合调控关系（均P < 0.05）。敲减SNHG14可明显抑制Huh7细胞的增殖、迁移、侵袭、PCNA、vimentin、SPARC mRNA及蛋白的表达（均P < 0.05），促进细胞凋亡、miR-579-3p和E-cadherin表达（均P < 0.05）；抑制miR-579-3p则可部分逆转敲减SNHG14对Huh7细胞的作用（均P < 0.05）。结论：敲减SNHG14可通过靶向miR-579-3p/SPARC轴抑制Huh7细胞的恶性生物学行为，促进其凋亡；SNHG14和miR-579-3p/SPARC轴可能是HCC治疗的潜在靶点。

BACKGROUND: The relationship between glycated hemoglobin (HbA1c) and cognitive impairment in older adults with coronary heart disease (CHD) remains unclear. METHODS: The present study used a prospective cohort study design and included 3244 participants aged ≥ 65 years in Beijing, China. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess cognitive function. Serum HbA1c was detected at admission. All patients were divided into high HbA1c group (≥ 6.5 mmol/L) and low HbA1c group (< 6.5 mmol/L) based on their HbA1c levels. Logistic regression analyses were used to evaluate the association between HbA1c and cognitive impairment. RESULTS: In this study of 3244 participants, 1201 (37.0%) patients were in high HbA1c group and 2045 (63.0%) patients were in a state of cognitive impairment. Logistic regression analyses demonstrated that HbA1c was an independent risk factor for cognitive impairment regardless of whether the HbA1c was a continuous or categorical variable (OR = 1.27, 95% CI: 1.15-1.40, P < 0.001; OR = 1.79, 95% CI: 1.41-2.26, P ≤ 0.001, respectively). The restricted cubic spline curve exhibited that the relationship between the HbA1c and cognitive impairment was linear (p for non-linear = 0.323, P < 0.001). CONCLUSION Elevated levels of HbA1c were associated with an increased risk of cognitive impairment in older patients with CHD. These insights could be used to improve the accuracy and sensitivity of cognitive screening in these patient populations.

OBJECTIVE: To evaluate the safety and effectiveness of robot-assisted percutaneous coronary intervention (R-PCI) compared to traditional manual percutaneous coronary intervention (M-PCI). METHODS: This prospective, multicenter, randomized controlled, non-inferior clinical trial enrolled patients with coronary heart disease who met the inclusion criteria and had indications for elective percutaneous coronary intervention. Participants were randomly assigned to either the R-PCI group or the M-PCI group. Primary endpoints were clinical and technical success rates. Clinical success was defined as visually estimated residual post-percutaneous coronary intervention stenosis < 30% with no 30-day major adverse cardiac events. Technical success in the R-PCI group was defined as successful completion of percutaneous coronary intervention using the ETcath200 robot-assisted system, without conversion to M-PCI in the event of a guidewire or balloon/stent catheter that was unable to cross the vessel or was poorly supported by the catheter. Secondary endpoints included total procedure time, percutaneous coronary intervention procedure time, fluoroscopy time, contrast volume, operator radiation exposure, air kerma, and dose-area product. RESULTS: The trial enrolled 152 patients (R-PCI: 73 patients, M-PCI: 79 patients). Lesions were predominantly B2/C type (73.6%). Both groups achieved 100% clinical success rate. No major adverse cardiac events occurred during the 30-day follow-up. The R-PCI group had a technical success rate of 100%. The R-PCI group had longer total procedure and fluoroscopy times, but lower operator radiation exposure. The percutaneous coronary intervention procedure time, contrast volume, air kerma, and dose-area product were similar between the two groups. CONCLUSIONS For certain complex lesions, performing percutaneous coronary intervention using the ETcath200 robot-assisted system is safe and effective and does not result in conversion to M-PCI.

Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.
Humans ; Cochlear Implantation ; Prognosis ; Hearing Loss/surgery* ; Consensus ; Connexin 26 ; Mutation ; Sulfate Transporters ; Connexins/genetics*

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

Aim To investigate the effect of safflower yellow (SY) on learning and memory ability of APP/ PS1 mice at different disease stages, and to explore the mechanism of SY anti- Alzheimer's disease by using 3-,6- and 9-month-old APP/PS 1 transgenic mice as experimental animal models. Methods Behavioral experiments were conducted to observe the effects of SY on learning and memory of APP/PS1 mice of different months. ELISA was used to detect the effect of SY on the expression of inflammatory factors in cortex of mice of different months. Western blot was used to detect the microglia activation marker protein, and its mechanism of action was further analyzed. Results SY could enhance the learning and memory ability of mice aged 3, 6 and 9 months, reduce the content of IL-6 and increase the content of TGF-β1 in brain tissue, up-regulate the expression levels of arginase-1 (arg-1) and triggering receptor expressed on myeloid cells 2 (tREM2) in brain tissue of mice of different months, and down-regulate the expression levels of inducible nitric oxide synthase (iNOS), Toll-like receptors 4 (tlr4) and nuclear factor-kappa B (nf-KB). Conclusions Compared with 3- and 9-month-old mice, SY is the most effective in improving learning memory in 6-month-old APP/PS1 mice. SY inhibits TLR4/NF-KB pathway activation by inducing TREM2 expression in brain tissue of APP/PS 1 transgenic mice, promotes microglia phenotype shift to anti-inflammatory phenotype, reduces chronic neuroinflammatory response, and improves learning memory in APP/PS1 mice at all months of age.

Ankylosing spondylitis (AS) combined with lower cervical fracture is often categorized into unstable fracture, with a high incidence of neurological injury and a high rate of disability and morbidity. As factors such as shoulder occlusion may affect the accuracy of X-ray imaging diagnosis, it is often easily misdiagnosed at the primary diagnosis. Non-operative treatment has complications such as bone nonunion and the possibility of secondary neurological damage, while the timing, access and choice of surgical treatment are still controversial. Currently, there are no clinical practice guidelines for the treatment of AS combined with lower cervical fracture with or without dislocation. To this end, the Spinal Trauma Group of Orthopedics Branch of Chinese Medical Doctor Association organized experts to formulate Clinical guidelines for the treatment of ankylosing spondylitis combined with lower cervical fracture in adults ( version 2024) in accordance with the principles of evidence-based medicine, scientificity and practicality, in which 11 recommendations were put forward in terms of the diagnosis, imaging evaluation, typing and treatment, etc, to provide guidance for the diagnosis and treatment of AS combined with lower cervical fracture.

Objective:To explore the efficacy of online pulmonary rehabilitation (PR) management among community-dwelling patients with stable chronic obstructive pulmonary disease (COPD).Methods:This study was a single-center randomized controlled trail with an unblinded design. A total of 130 patients with stable COPD who visited Zhuanqiao Community Health Service Center in Shanghai Minhang District from October 2020 to March 2022 were randomly divided into study group and control group with 65 cases in each group. Both groups received conventional treatment, while patients in study group attended online rehabilitation management, including face-to-face rehabilitation instruction and multiple online guidance. Pulmonary ventilation function including forced vital capacity (FVC), forced expiratory volume in the first second (FEV 1) and percentage of forced expiratory volume in the first second to forced expiratoty volume (FEV 1%pred), modified British Medical Research Council Dyspnea Scale (mMRC), chronic obstructive pulmonary disease assessment test (CAT), score of 6 minutes walking distance (6MWD) and DOSE (dyspnea, degree of airflow obstruction, smoking status, the number of exacerbation) index were measured at baseline and after 8 weeks of rehabilitation, and compared between two groups. Results:The baseline data of the two groups were comparable. After 8 weeks of management, FVC, FEV 1, FEV 1%pred, mMRC, CAT, 6MWD and DOSE index of both groups were improved compared with the baseline level(control group: t=-7.799, -7.581, -9.010, 3.565, 9.887, -16.677, 3.795; study group: t=-12.623, -13.914, -17.644, 7.404, 22.457, -26.826, 7.968; all P<0.05). The FEV 1%pred, CAT and 6MWD in the study group were better than those in the control group ( t=-2.939, 2.277,-2.130, all P<0.05); while there were no significant differences in FVC, FEV 1, mMRC and DOSE index between the two groups( t=-0.162, -1.280, 0.925, 1.939,all P>0.05). Conclusions:The online pulmonary rehabilitation management can better improve lung function, dyspnea symptoms and exercise tolerance of patients with stable COPD, which can be used for rehabilitation training and management of community-dwelling patients.