Osteosarcoma (OS) is the most common primary malignant bone tumor. Conventional treatment relies on surgical resection followed by Poly (methyl methacrylate) (PMMA) bone cement filling. However, the bioinertness of PMMA and the inhibitory microenvironment often suppress the bone repair and eradication of OS. In this study, the PMMA modified with magnetic bioactive glass (PMBG) was synthesized with favorable mechanical properties and multiple biological functions. Through the incorporation of magnetic bioactive glass (MBG), PMBG enabled the sustained release of Ca2+, enhanced surface hydrophilicity and optimized the microporous architecture of the PMMA, which promoted the adhesion and differentiation of osteoblasts. Furthermore, leveraging its favorable magnetothermal properties, PMBG demonstrated promising potential for mild hyperthermia treatment against tumor cells. Consequently, it enhanced osseointegration in bone defects and achieved effective tumor ablation in vivo. The present study provides a unique bioactive bone cement as a promising alternative strategy for the bone repair in weight-bearing regions after tumor resection.

BACKGROUND:Atherosclerosis (AS), the primary pathophysiological foundation of coronary artery disease (CAD), initiates through endothelial dysfunction that facilitates lipid deposition and plaque formation. Emerging evidence implicates dipeptidyl peptidase IV (DPP4) in vascular pathologies, yet its mechanistic role in AS-associated endothelial ferroptosis remains undefined. METHODS:Multidisciplinary approaches were employed: 1) Bioinformatic analysis of public databases identified DPP4-ferroptosis-AS associations; 2) Clinical samples measured plasma DPP4 levels across CAD severity strata; 3) Atherogenic progression was compared between DPP4-/-ApoE-/- and ApoE-/- mice under a high-fat diet; 4) Ox-LDL-induced endothelial injury models assessed DPP4-mediated ferroptosis mechanisms combining proteomics, cycloheximide chase assays, and pharmacological modulation of autophagy. RESULTS:Clinical samples analysis revealed a significant increase in plasma DPP4 levels in patients with severe coronary artery stenosis, with DPP4 enrichment observed at plaque. Animal studies demonstrated that DPP4 deficiency attenuated progression of AS and ferroptosis in murine models. Cellular experiments revealed ox-LDL upregulated DPP4 expression, concomitant with increased ferroptosis susceptibility and endothelial dysfunction. DPP4 inhibition preserved endothelial viability by blocking lipid peroxide accumulation. Mechanistically, mouse proteomics revealed that ferroptosis and autophagy pathways were associated with DPP4 in AS. DPP4 destabilized FTH1 via NCOA4-mediated ferritinophagy, proven by concordant rescue effects of chloroquine (autophagy inhibition) and saxagliptin (DPP4 inhibition) on FTH1 preservation. CONCLUSIONS:This study establishes endothelial DPP4 as a regulator of ferritinophagy-driven ferroptosis, inducing endothelial dysfunction in AS. Our findings propose targeting the DPP4-NCOA4-FTH1 axis as a promising strategy to preserve endothelial viability and halt early AS progression, with translational implications for repurposing DPP4 inhibitors in cardiovascular therapeutics.

Extracellular vesicles (EVs) represent promising cell-free therapeutics for the regeneration of aged bone defects. Mechanical stimulation is critical in bone regeneration and significantly influences both EV secretion and cargo composition. Despite this, translating mechanically programmed EVs to clinically relevant doses remains a significant challenge. Most current scalable bioreactor systems has achieved high yields through high-density cell culture and fluid flow, yet they do not provide programmable or spatially consistent mechanical stimulation. In this study, an electrospun scaffold-enabled bioreactor was developed to integrate high-density three-dimensional macrophage culture with programmable cyclic stretching, enabling simultaneous EV scale-up and cargo programming. The interconnected fiber junction network transmits boundary-applied strain with enhanced spatial consistency, while the highly porous scaffold supports dense cell seeding and efficient EV release and collection. This approach increases EV yield by 13.8-fold compared to conventional two-dimensional culture. Fiber-mediated mechanical conditioning activates Piezo1-dependent Ca2+ signaling and integrin-associated mechanotransduction, promotes Yes-associated protein (YAP) nuclear translocation, and remodels EV cargo composition. The resulting mechanically stimulated EVs (ms-EVs) demonstrate concurrent pro-regenerative activities, including cellular rejuvenation, vascular repair, and osteogenic enhancement, and perform favorably compared to canonical interleukin-4 (IL-4)-polarized M2 macrophage-derived extracellular vesicles (M2-EVs). In aged rat femoral defects, ms-EV-functionalized scaffolds increase bone volume fraction by approximately 1.7-fold at 8 weeks, reduce p16+ senescent cells, and enhance CD31+ neovascularization. These findings establish electrospun scaffolds as scalable mechanobiological manufacturing substrates for the production of functionally programmed EV therapeutics.

Sonodynamic therapy (SDT) has enormous potential to eradicate tumors in situ and reshape antitumor immunity, but the efficacy of SDT is constrained by sonosensitizer performance and the intensity of the induced immune response. In the present study, a metal-organic framework (MOF) sonosensitizer (PN20@Rx) for treating bone metastases was designed through alendronate sodium (ALN)-mediated defect engineering. This strategy significantly increased sonocatalytic efficiency by narrowing the interstitial spaces and optimizing the sonic-to-electrical energy conversion. Furthermore, PN20@Rx exhibited multiple nanoenzyme activities and bone-targeting properties, simultaneously depleting glutathione (GSH), generating hydroxyl radicals (•OH), and producing oxygen (O2). In a bone metastasis model, upon ultrasound (US) stimulation, PN20@Rx effectively cleared 4T1 cells within mouse tibiae, inhibited tumor-associated bone destruction, and induced multiple regulated cell death (RCD) pathways and immunogenic cell death (ICD). PN20@Rx simultaneously downregulated the expression of the CD47 immune checkpoint protein on tumor cell surfaces, thereby converting the tumor from an immune "cold" state to an immune "hot" state and effectively suppressing lung metastasis. The present study provides a unique sonocatalytically enhanced strategy and novel insights for MOF-based clinical tumor immunotherapy.

Osteoporosis, a systemic skeletal disorder characterized by reduced bone density and increased fracture risk, poses a significant global health challenge. While teriparatide (TRP), a first-line anabolic peptide drug, demonstrates substantial therapeutic benefits in osteoporosis management, its clinical use is restricted by the necessity for daily subcutaneous administration, leading to suboptimal patient compliance. To overcome this limitation, we developed an orally deliverable TRP formulation using biocompatible metal-organic framework nanoparticles (MOF-808 NPs) co-loaded with TRP and functionalized with transferrin targeting ligands (M@P@T NPs). The rationally designed nanoporous architecture coupled with transferrin surface modification synergistically protects TRP from acidic and enzymatic degradation in harsh gastrointestinal environments, while realizing controlled release of TRP in the phosphate-rich bloodstream. Leveraging the overexpression of transferrin receptors (TfR) on intestinal epithelial cells, the nanosystem facilitates receptor-mediated transcellular transport, enabling efficient systemic delivery of TRP with high oral bioavailability. After the one-month oral administration of low-dose M@P@T (200 μg kg-1·day-1) to osteoporosis model mice, therapeutic outcomes comparable to those achieved with subcutaneous TRP injections were observed, including increased bone mineral density, improved trabecular structure, and significant alleviation of osteoporosis symptoms. These findings suggest that this MOF-based oral TRP strategy has great potential for simplifying and improving the treatment of osteoporosis.

Extracellular vesicles (EVs) hold promise for tissue regeneration, but their low yield and limited therapeutic efficacy hinder clinical translation. Bioreactors provide a larger culture surface area and stable environment for large-scale EV production, yet their ability to enhance EV therapeutic efficacy is limited. Physical stimulation, by inducing cell differentiation and modulating EV cargo composition, offers a more efficient, cost-effective, and reproducible approach compared to the cargo loading of EVs and biochemical priming of parental cells. Herein, the effects of a 3D-printed perfusion bioreactor with a topographical cue on the macrophage EV yield and bioactivity were assessed. The results indicate that the bioreactor increased the EV yield 12.5-fold and enhanced bioactivity in promoting osteogenic differentiation and angiogenesis via upregulated miR-210-3p. Mechanistically, fluid shear stress activates Piezo1, triggering Ca2+ influx and Yes-associated protein (YAP) nuclear translocation, promoting EV secretion and enhancing macrophage M2 polarization in conjunction with morphological changes guided by aligned topography. Moreover, a porous electrospun membrane-hydrogel composite scaffold loaded with bioreactor-derived EVs exhibited outstanding efficacy in promoting osteogenic differentiation and angiogenesis in a rat cranial defect model. This study presents a scalable, cost-effective, and stable platform for the production of therapeutic EVs, potentially overcoming key challenges in translating EV-based therapies to the clinic.

Purpose:In essential hypertensive patients, cardiac remodeling may be associated with the risk of renal damage in the future which can be reflected by the estimated glomerular filtration rate (eGFR). Through retrospective analysis, we evaluated the potential of cardiac remodeling based on echocardiographic measurements to predict the risk of renal damage in the future with hypertensive patients.Methods:We retrospectively analyzed the relationship between the changes of left heart structure and function and renal damage for 510 patients with hypertension, who were diagnosed between 2016 to 2022. Demography data, clinical data, blood samples and echocardiographic variables were used for survival analysis, and the Cox proportional hazards regression model was used.Results:In our study, we found that age, serum creatinine (SCR), creatine kinase isoenzyme MB (CK MB), abnormal high-sensitivity troponin I (TNI), interventricular septum thickness (IVST) and left ventricular ejection fraction (LVEF) could be used as independent predictors in risk of renal impairment in hypertensive patients (p<0.05). Combined in a score where one point was given for the presence of each of the parameters above, this score could strongly predict renal function damage in the future (p<0.05). In receiver operating characteristics (ROC) curve analyses, the area under the curve of the risk factor score was 0.849 (P<0.001).Conclusion:In essential hypertensive patients, LVEF and IVST can predict the risk of future adverse renal outcomes. Moreover, combining risk variables into a simplified score may enable to assess the risk of renal impairment in hypertensive patients at an early stage.

Personalized repair of bone defects remains a tremendous clinical challenge. Developing 3D-printed bioceramics with excellent osteogenic potential is an effective therapeutic strategy to overcome this challenge. In this study, we prepared composite bioceramics (designated as CSC-DBM) with immunomodulatory, vascularization, and osteogenesis based on calcium silicate (CS) bioceramics, calcium sulfate (CSH), and decalcified bone matrix (DBM). CSC-DBM bioceramics has an unmatched biomineralization potential due to the synergistic promotion of CS and CSH. Meanwhile, CSC-DBM bioceramics could effectively modulate the immune response, induce M2 macrophage polarization, promote vascular regeneration, and further enhance new bone formation. In summary, this composite bioceramics made of CS bioceramics, CSH, and DBM can provide a new solution for bone defect repair in the clinic.

The ideal tissue engineering scaffold should facilitate rapid cell infiltration and provide an optimal immune microenvironment during interactions with the host. Electrospinning can produce two-dimensional (2D) membranes mimicking the extracellular matrix. However, their dense structure hinders cell penetration, and their thin form restricts scaffold utility. In this study, latticed hydrogels were three-dimensional (3D) printed onto electrospun membranes. This technique allowed for layer-by-layer assembly of the membranes into 3D scaffolds, which maintained their resilience impressively under both dry and wet conditions. We assessed the cellular and host responses of these 3D nanofiber scaffolds by comparing random membranes and mesh-like membranes with three different mesh sizes (250, 500, and 750 μm). It was found that scaffolds with a mesh size of 500 μm were superior for M2 macrophage phenotype polarization, vascularization, and matrix deposition. Furthermore, it was confirmed by subsequent experiments such as RNA sequencing that the mesh-like topology may promote polarization to the M2 phenotype by affecting the PI3K/AKT pathway. In conclusion, our work offers a novel method for transforming 2D nanofiber membranes into 3D scaffolds. This method boasts flexibility, allowing for the use of varied electrospun membranes and hydrogels in terms of structure and composition. It has vast potential in tissue repair and regeneration.

The complex genomics, immunosuppressive tumor microenvironment (TME), and chemotherapeutic resistance of osteosarcoma (OS) have resulted in limited therapeutic effects in the clinic. Ferroptosis is involved in tumor progression and is regulated mainly by glutathione peroxidase 4 (GPX4). Small interfering RNA (siRNA)-based RNA interference (RNAi) can precisely target any gene. However, achieving effective siRNA delivery is highly challenging. Here, we fabricated a TME-responsive metal-organic framework (MOF)-based biomimetic nanosystem (mFeP@si) with siGPX4 delivery and sonodynamic therapy (SDT) to treat OS by targeting ferroptosis. Under ultrasound (US) irradiation, mFeP@si achieves lysosomal escape via singlet oxygen (1O2)-mediated lysosomal membrane disruption and then accelerates ROS generation and glutathione (GSH) depletion. Meanwhile, siGPX4 silences GPX4 expression by binding to GPX4 mRNA and leads to the accumulation of toxic phospholipid hydroperoxides (PL-OOH), further magnifying the ROS storm and triggering ferroptosis. Notably, synergistic therapy remarkably enhances antitumor effects, improves the immunosuppressive TME by inducing potent immunogenic cell death (ICD), and increases the sensitivity of chemotherapy-resistant OS cells to cisplatin. Overall, this novel nanosystem, which targets ferroptosis by integrating RNAi and SDT, exhibits strong antitumor effects both in vitro and in vivo, providing new insights for treating OS.

The metastasis and recurrence of osteosarcoma (OS) are significant challenges in its clinical management. Tumor immunogenic cell death (ICD)-induced immunotherapy has been widely investigated to solve these problems. However, achieving sufficient ICD and a robust immune response is challenging for nanoparticle-based OS immunotherapy. Here, we report an ultrasound -responsive metal -organic framework -based nanosystem (MFePCN@1-MT) with sonodynamic therapy (SDT) and 1-methyltryptophan (1 -MT) responsive release properties. Under ultrasound irradiation, the nanosystem induces reactive oxygen species (ROS) generation, ferroptosis, and the responsive release of 1 -MT, which competitively inhibits indoleamine-2,3-dioxygenase (IDO), promotes further ROS accumulation, and amplifies ferroptosis. Notably, SDT/amplified ferroptosis/IDO blockade synergistically kills OS cells, maximizes the amplified ICD effect, activates dendritic cells (DCs) maturation, inhibits regulatory T lymphocytes (Tregs), and triggers CD4 + T -cell and CD8 + T -cell immune responses. Thus, this nanosystem synergistically inhibits K7M2 primary tumors via SDT/amplified ferroptosis/IDO blockade. In addition, the nanosystem enhances the ICD effect, modulates the immunosuppressive microenvironment, promotes immunity against solid tumors, and inhibits distant metastatic tumor growth. This study combines SDT/ amplified ferroptosis/IDO blockade into a single nanomedicine and presents a new strategy for OS immunotherapy.

Osteoporosis is a degenerative disease caused by an imbalance between osteoblast and osteoclast activity. Repairing osteoporotic bone defects is challenging due to decreased osteogenesis, increased osteoclast activity, and impaired angiogenesis. To address this challenge, a novel scaffold, inspired by the structure of multilayer fishing nets, is developed through a combination of template-assisted electrospinning and advanced three-dimensional (3D) printing technologies. The 3D nanofiber scaffold exhibits a hierarchical porous architecture. This design maintains the high specific surface area and extracellular matrix (ECM) mimicry of the nanofiber membrane. Additionally, the sparsely distributed nanofibers within the mesh-like structure facilitate cell infiltration. This unique topological configuration, particularly the strontium-hydroxyapatite (Sr-HAp)-enriched polycaprolactone/silk fibroin nanofibers, plays a critical role in synergistically promoting angiogenesis, enhancing osteogenesis, and suppressing osteoclast differentiation. In an osteoporotic cranial bone defect model, the scaffold demonstrates an exceptional repair efficiency of nearly 100% within 8 weeks, marked by significant new bone formation throughout the implanted area. In conclusion, our approach, which leverages intricate biomimicry and strategic active ion release, emerges as a highly promising strategy for repairing osteoporotic bone defects.

There are still limitations in artificial bone materials used in clinical practice, such as difficulty in repairing large bone defects, the mismatch between the degradation rate and tissue growth, difficulty in vascularization, an inability to address bone defects of various shapes, and risk of infection. To solve these problems, our group designed stereolithography (SLA) 3D-printed calcium silicate artificial bone improved by a calcium sulfate-Cu2+ delivery system. SLA technology endows the scaffold with a three-dimensional tunnel structure to induce cell migration to the center of the bone defect. The calcium sulfate-Cu2+ delivery system was introduced to enhance the osteogenic activity of calcium silicate. Rapid degradation of calcium sulfate (CS) induces early osteogenesis in the three-dimensional tunnel structure. Calcium silicate (CSi) which degrades slowly provides mechanical support and promotes bone formation in bone defect sites for a long time. The gradient degradation of these two components is perfectly matched to the rate of repair in large bone defects. On the other hand, the calcium sulfate delivery system can regularly release Cu2+ in the temporal and spatial dimensions, exerting a long-lasting antimicrobial effect and promoting vascular growth. This powerful 3D-printed calcium silicate artificial bone which has rich osteogenic activity is a promising material for treating large bone defects and has excellent potential for clinical application.

Objective To evaluate the effect of atrial fibrillation（AF） on the outcomes of mitral regurgitation（MR） using Mitraclip. Methods Data-bases of PubMed, Cochrane Library, CNKI,Wanfang data and other databases were searched through computer, clinical studies that met the inclusion criteria were included. The statistical analysis was conducted by using Rev Man 5.4software. Results Eight clinical trials were finally enrolled with a total of 22949 patients, of whom 12246 were assigned to MR+AF group and 10703 to MR+non-AF group. Meta-analysis results showed that the all-cause mortality after MitraClip implanation in the MR+AF group was higher than that in the MR+non-AF group（OR=1.41, 95%CI:1.28-1.55, P＜0.05）, the procedural failure（OR=1.04, 95%CI:0.86-1.24）, heart failure related hospitalization（OR=1.42, 95%CI:0.99-2.05） and stroke（OR=1.05, 95%CI:0.43-2.57） between two groups were not statistically significant（all P＞0.05）. Conclusion Atrial fibrillation is a risk factor for all-cause death after MitraClip implanation in patients with MR, but the effect of other ectopic rhythm on MitraClip interventional therapy needs further study.

Bone defects and tumor cell residues after bone tumor resection have always been a challenge. We tried to investigate a kind of bioglass with both bone repair and tumor killing capability to achieve two birds with one stone. We used a Sol-Gel method to prepare the high porous magnetic bioglass (MBG) and then compounded the MBG with calcium sulfate (CS) bone cement to form the composite scaffold (CS-MBG). We found that the CS-MBG could reach about 43 °C under the condition of magnetic field in vitro. Under this condition, CS-MBG would release Ca2+ resulting in the cell death of calcium overload. Meanwhile, the suitable pH and osteogenic activity of CS-MBG can promote the postoperative bone repair and inhibit the growth of bone tumors. Our work has innovatively designed a magnetic bioglass and verified its mechanism of synergistic hyperthermia against tumor, providing a new idea for the treatment of tumor bone defects with magnetic bioglass.

The topographic cues of wound dressings play important roles in regulating cellular behaviors, such as cellular migration and morphology, and are capable of providing a prolonged stimulus for promoting wound healing. However, 3D porous dressings that can guide wound healing from the periphery to the center are poorly studied. Herein, radial sponges with adjustable lamellar spacing and microridge spacing by ice templating are developed to facilitate wound healing. With denser lamellae and microridges, fibroblasts achieve a more orderly arrangement, a larger elongation, and a greater migration rate. Meanwhile, the elongated state enables human umbilical vein endothelial cells to vascularization. The faster healing rate and a higher degree of vascularization based on radial sponges are further demonstrated in full-thickness skin defects in rats. Taken together, radial sponges with the densest lamellae and microridges perform the best in guiding the wound from the periphery to the center of the repair environment. It is believed that the proposed structure here can be combined with various biochemical factors to provide dressings with functions.

Ferroptosis regulators have been found to affect tumor progression. However, studies focusing on ferroptosis and soft tissue sarcoma (STS) are rare. Somatic mutation, copy number variation, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, consensus clustering, differentially expressed genes analysis (DEGs), principal component analysis (PCA) and gene set enrichment analysis (GSEA) were used to identify and explore different ferroptosis modifications in STS. A nomogram was constructed to predict the prognosis of STS. Moreover, three immunotherapy datasets were used to assess the Fescore. Western blotting, siRNA transfection, EdU assay and reactive oxygen species (ROS) measurement were performed. 16 prognostic ferroptosis regulators were screened and significant differences were observed in somatic mutation, copy number variation (CNV) and RT-qPCR among these ferroptosis regulators. 2 different ferroptosis modification patterns were found (Fe cluster A and B). Fe cluster A with higher Fescore was correlated with p53 pathway and had better prognosis of STS (p = 0.002) while Fe cluster B with lower Fescore was correlated with angiogenesis and MYC pathway and showed a poorer outcome. Besides, the nomogram effectively predicted the outcome of STS and the Fescore could also well predict the prognosis of other 16 tumors and immunotherapy response. Downregulation of LOX also inhibited growth and increased ROS production in sarcoma cells. The molecular characterization of ferroptosis regulators in STS was explored and an Fescore was constructed. The Fescore quantified ferroptosis modification in STS patients and effectively predicted the prognosis of a variety of tumors, providing novel insights for precision medicine.

目的 系统评价压力反射激活疗法(BAT)治疗射血分数降低型心力衰竭(HFrEF)的有效性和安全性.方法 计算机检索PubMed、Embase、Cochrane Library、Web of Science、万方数据知识服务平台和中国知网等数据库,检索关于BAT治疗HFrEF的随机对照试验.筛选文献和偏倚风险评价后,采用RevMan 5.4软件进行Meta分析.结果 最终纳入6项文献共10项研究.Meta分析结果显示:BAT组的6 min步行距离改善情况、美国纽约心脏病协会心功能分级改善情况、心力衰竭再住院次数、心力衰竭再住院持续时间均优于对照组(均P<0.05),而两组在降低全因死亡率,以及改善生活质量评分和左室射血分数方面的差异均无统计学意义(均P>0.05).结论 BAT能改善HFrEF患者的心功能和运动耐量,降低患者心力衰竭再住院风险,但仍需更多大样本的随机对照试验证实所得结论.

This study was undertaken to determine if coronary computed tomographic angiography (CCTA) can help to assess patent foramen ovale (PFO) with high accuracy and reproducibility when compared to transesophageal echocardiography (TEE). In total, 75 suspected PFO cases (31 men, 44 women; mean age, 45 ± 9 years) were evaluated by coronary CTA and TEE. PFO tunnel length (TL) and the opening diameter of the left atrial entrance (ODLAE) and right atrial entrance (ODRAE), as well as contrast shunt (if present due to PFO), were measured by both modalities. PFO was detected in 68 patients with TEE. The sensitivity for the detection of PFO with CCTA was 85.3%; specificity, 71.4%; positive predictive value, 96.7%; and negative predictive value, 33.3%. Both modalities demonstrated good agreement in measuring TL and ODLAE of PFO. However, the ODRAE of TEE was different from that of CCTA (1.14 ± 0.4 mm and 1.45 ± 0.5 mm, respectively, p = 0.04). The intra-observer and inter-observer variability and agreement for TL, ODRAE, and ODLAE of PFO were excellent between the two measurements. CCTA provided a method for detection of PFO with high accuracy and reproducibility compared with TEE. Therefore, CCTA is a practical and efficient alternative to TEE for PFO diagnosis.