Reversing immunosuppression and establishing durable immunological memory remain critical challenges in oral squamous cell carcinoma. This study presents a sequential "AND" logic-gated immunotherapeutic nano-platform that orchestrates intracellular delivery, immunogenic cell death, and efferocytosis inhibition in response to defined input signals to establish robust and durable antitumor immunity. This nanoplatform is constructed from core-shell nanoparticles co-encapsulating the mitochondria-targeting photosensitizer IR780 and the efferocytosis inhibitor Annexin A5. The "AND" logic-gated strategy is governed by three defined input signals. Under the first "AND" logic gate, precise intracellular delivery is achieved via acidic and reductive tumor microenvironmental cues, while subsequent mitochondrial oxidative stress is induced by near-infrared laser irradiation. These two events converge to trigger pyroptosis-dominant immunogenic cell death and concurrently generate apoptotic cells with exposed phosphatidylserine. Under the second "AND" logic gate, intracellularly released Annexin A5 converges with exposed phosphatidylserine, converting immunologically silent apoptosis into inflammatory secondary necrosis. Finally, pyroptosis and secondary necrosis integrate under the third "AND" logic gate to amplify antigen release, thereby reversing immunosuppression and promoting cytotoxic T lymphocyte infiltration. This sequential "AND" logic-gated cascade stringently governs the reprogramming of cell death pathways. The strategy ultimately achieved a 66.4% inhibition rate in the oral squamous cell carcinoma model, while also inducing durable immunological memory that maintained potent antitumor immunity at 45 days post-treatment. Moreover, the nanoplatform exhibited synergistic efficacy with anti-PD-1 therapy and demonstrated antitumor activity in other immunosuppressive tumor models, underscoring its broad applicability and establishing a foundational framework for next-generation precision immunotherapy platform.

The metabolic microenvironment plays important roles in tumorigenesis, but how leukemia-initiating cells (LICs) response to the acidic BM niche remains largely unknown. Here, we show that acid-sensing ion channel 3 (ASIC3) dramatically delays leukemogenesis. Asic3 deletion results in a remarkably enhanced self-renewal, reduced differentiation, and 9-fold greater number of murine acute myeloid LICs. We developed an ultrasensitive, ratiometric, genetically encoded fluorescent pH sensor (pHluorin3) and demonstrated that LICs prefer localizing in the endosteal niche with a neutral pH range of 7.34-7.42, but not in the vascular niche with a lower pH range of 6.89-7.22. Unexpectedly, acid-ASIC3 signaling inhibits both murine and human LIC activities in a noncanonical manner by interacting with the N-terminal of STIM1 to reduce calcium-mediated CAMK1-CREB-MEIS1-LDHA levels, without inducing cation currents. This study reveals a pathway in suppression of leukemogenesis in the acidic BM niche and provides insight into targeting LICs or other cancer stem cells through pH-dependent ASICs.

Certain secretory proteins are known to be critical for maintaining the stemness of stem cells through autocrine signaling. However, the processes underlying the biogenesis, maturation, and secretion of these proteins remain largely unknown. Here we demonstrate that many secretory proteins produced by hematopoietic stem cells (HSCs) undergo exosomal maturation and release that is controlled by vacuolar protein sorting protein 33b (VPS33B). Deletion of VPS33B in either mouse or human HSCs resulted in impaired exosome maturation and secretion as well as loss of stemness. Additionally, VPS33B deficiency led to a dramatic delay in leukemogenesis. Exosomes purified from either conditioned medium or human plasma could partially rescue the defects of HSCs and leukemia-initiating cells (LICs). VPS33B co-existed in exosomes with GDI2, VPS16B, FLOT1, and other known exosome markers. Mechanistically, VPS33B interacted with the GDI2/RAB11A/RAB27A pathway to regulate the trafficking of secretory proteins as exosomes. These findings reveal an essential role for VPS33B in exosome pathways in HSCs and LICs. Moreover, they shed light on the understanding of vesicle trafficking in other stem cells and on the development of improved strategies for cancer treatment.

Biodegradable magnesium (Mg)-based materials show promise for orthopedic implants but continue to face challenges such as limited mechanical strength, rapid corrosion, and insufficient osteogenic performance. Alloying offers a practical solution by improving these properties and mitigating their rapid degradation in physiological environments. In this study, we designed novel Mg-Zn-Mn-Ca alloys with 2 wt% and 3 wt% Zn (referred to as Mg2Zn and Mg3Zn), harnessing the synergistic effects of Zn, Mn, and Ca to enhance mechanical properties, corrosion resistance, and biological performance. Both alloys outperformed pure Mg in mechanical tests; notably, Mg3Zn achieved an ultimate tensile strength of 206.5 MPa and an elongation of 30.1 %, underscoring a balance of strength and ductility. Corrosion analysis showed that Mg3Zn had the lowest corrosion rate (1.17 mm/year) and formed compact, insoluble corrosion products. Regarding osteogenic potential, Mg2Zn enhanced Runx2 expression 1.69-fold, while Mg3Zn increased Ocn expression 1.95-fold relative to the control, with Mg3Zn consistently showing higher osteogenic capacity. Altogether, Mg-Zn-Mn-Ca alloys demonstrated enhanced mechanical properties and excellent osteogenic potential, with the 3 wt% Zn alloy providing superior corrosion resistance and mid-to-late-stage osteogenesis. These findings position Mg3Zn as a strong candidate for biodegradable metallic orthopedic implants with significant clinical potential.

The remodeling of macrophages mediated by biomaterials is an important step in osseointegration. The biointerfacial characteristics shaped by implants and the bioenergetic state derived from macrophages are considered the key to macrophage reprogramming. In this study, the integrated Ti/Zn composites with optimized morphology and bioactive phase were prepared by friction stir processing, which could meet the multi-biofunctional requirements in the application of narrow-diameter implants. The severe plastic deformation and the hindrance of Zn particles to grain growth promote grain refinement, resulting in enhanced mechanical properties. The cell interfacial adhesion mediated by the grain boundary collaborated the energy metabolism reprogramming induced by the released Zn ion, promoting jointly anti-inflammatory cascade in macrophages and favorable osteogenesis in bone marrow mesenchymal stem cells (BMSCs). This study provides a new simultaneous approach of morphology and composition modification for titanium implants, and reveals the important role of grain size and bioactive element in the reversion of macrophage fate as well.

Acute stress (AS) exposure and traumatic brain injury (TBI) have a high prevalence and result in emotional and behavioral impairments. In fact, TBI is a leading cause of mortality in young adults and survivors cope with neuropsychological sequelae including memory decline, addiction, anxiety and compromised stress responses. So far, the interaction of psychological stress with previous TBI is poorly understood. Herein, the impact of a previous TBI on AS responsiveness was investigated. For this, a model of mild TBI and restraint AS was employed and mice were grouped into sham, TBI alone, AS alone and TBI + AS cohorts. The impact of an initial TBI on subsequent AS was analyzed by immediate early gene (IEG) and neuroinflammatory gene expression as well as proteomics. In addition, behavioral consequences were monitored by open field, ladder walk and the Catwalk gait analysis. Finally, since both TBI and AS impinge on hypothalamus-pituitary-adrenal (HPA) axis regulation, CORT and ACTH levels were measured. We observed that some AS associated responses such as gene induction in the brain and HPA axis were largely unaffected by TBI occurring one day before AS exposure. In contrast, on the behavioral level, several AS associated locomotor alterations were modulated post-TBI. Hormone levels of the HPA axis were likewise modulated by the TBI and AS interaction. Finally, blood-derived proteomics identified proteins regulated by individual exposures as well as by the TBI and AS interaction. In summary, we demonstrate that previous TBI affects responsiveness to AS exposure on behavioral level and HPA axis regulation.

Osteoporosis is a prevalent metabolic bone disease. While drug therapy is essential to prevent bone loss in osteoporotic patients, current treatments are limited by side effects and high costs, necessitating the development of more effective and safer targeted therapies. Utilizing a zebrafish ( Danio rerio) larval model of osteoporosis, we explored the influence of the metabolite spermine on bone homeostasis. Results showed that spermine exhibited dual activity in osteoporotic zebrafish larvae by increasing bone formation and decreasing bone resorption. Spermine not only demonstrated excellent biosafety but also mitigated prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine showcased protective attributes in the nervous systems of both zebrafish embryos and larvae. At the molecular level, Rac1 was identified as playing a pivotal role in mediating the anti-osteoporotic effects of spermine, with P53 potentially acting downstream of Rac1. These findings were confirmed using mouse ( Mus musculus) models, in which spermine not only ameliorated osteoporosis but also promoted bone formation and mineralization under healthy conditions, suggesting strong potential as a bone-strengthening agent. This study underscores the beneficial role of spermine in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine are promising candidates for new anti-osteoporotic drug development and daily bone-fortifying agents.

The healing process of critical-sized bone defects urges for a suitable biomineralization environment. However, the unsatisfying repair outcome usually results from a disturbed intricate milieu and the lack of in situ mineralization resources. In this work, we have developed a composite hydrogel that mimics the natural bone healing processes and serves as a seedbed for bone regeneration. The oxidized silk fibroin and fibrin are incorporated as rigid geogrids, and amorphous calcium phosphate (ACP) and platelet-rich plasma serve as the fertilizers and loam, respectively. Encouragingly, the seedbed hydrogel demonstrates excellent mechanical and biomineralization properties as a stable scaffold and promotes vascularized bone regeneration in vivo. Additionally, the seedbed serves a succinate-like function via the PI3K-Akt signaling pathway and subsequently orchestrates the mitochondrial calcium uptake, further converting the exogenous ACP into endogenous ACP. Additionally, the seedbed hydrogel realizes the succession of calcium resources and promotes the evolution of the biotemplate from fibrin to collagen. Therefore, our work has established a novel silk-based hydrogel that functions as an in-situ biomineralization seedbed, providing a new insight for critical-sized bone defect regeneration.

Tissue regeneration is regulated by morphological clues of implants in bone defect repair. Engineered morphology can boost regenerative biocascades that conquer challenges such as material bioinertness and pathological microenvironments. Herein, a correlation between the liver extracellular skeleton morphology and the regenerative signaling, namely hepatocyte growth factor receptor (MET), is found to explain the mystery of rapid liver regeneration. Inspired by this unique structure, a biomimetic morphology is prepared on polyetherketoneketone (PEKK) via femtosecond laser etching and sulfonation. The morphology reproduces MET signaling in macrophages, causing positive immunoregulation and optimized osteogenesis. Moreover, the morphological clue activates an anti-inflammatory reserve (arginase-2) to translocate retrogradely from mitochondria to the cytoplasm due to the difference in spatial binding of heat shock protein 70. This translocation enhances oxidative respiration and complex II activity, reprogramming the metabolism of energy and arginine. The importance of MET signaling and arginase-2 in the anti-inflammatory repair of biomimetic scaffolds is also verified via chemical inhibition and gene knockout. Altogether, this study not only provides a novel biomimetic scaffold for osteoporotic bone defect repair that can simulate regenerative signals, but also reveals the significance and feasibility of strategies to mobilize anti-inflammatory reserves in bone regeneration.

Objective: Consumptive coagulopathy treatment and pain management are crucial for patients with venous malformations (VMs). Dabigatran etexilate, a nonevitamin K antagonist oral anticoagulant, has known advantages compared with low-molecular-weight heparin and vitamin K antagonists, including oral administration, a more consistent pharmacokinetics/pharmacodynamics profile, a better safety profile, and no need for coagulation surveillance. In the present study, we tested the efficacy and safety of dabigatran etexilate for consumptive coagulopathy treatment and pain management for patients with VMs. Methods: To investigate the efficacy and safety of dabigatran etexilate in treating localized intravascular coagulation (LIC) associated with VM, we retrospectively collected data for 19 outpatients with VM and LIC, who had been treated with dabigatran etexilate from September 2019 to June 2021. The patients provided oral informed consent and underwent biologic blood testing, routine examinations, and determination of coagulation function before and after treatment. The dosage of dabigatran etexilate was 110 mg twice daily for adults and 55 mg twice daily for children. Results: All 19 patients had benefited from dabigatran etexilate treatment with coagulation improvement and pain relief. Pain had improved in all 16 evaluable patients. The fibrinogen and D-dimer levels had improved in 18 of 19 patients. The fibrin degradation product level had improved in 10 of 14 patients. None of patients reported lesion regression, appearance changes, or improvement in mobility. No significant differences were found in the D-dimer, fibrinogen, and fibrin degradation product levels between the short-term (<10 days) and long-term ($10 days) use of the medication. Dabigatran etexilate was well tolerated by all patients. No bleeding event had occurred during follow-up. Conclusions: The results of our study have confirmed the efficacy and safety of dabigatran etexilate in treating pain and LIC in patients with VMs. Dabigatran etexilate is a suitable choice preoperatively to modify coagulation function and pain in patients with VMs. (J Vasc Surg Venous Lymphat Disord 2023;11:397-403.)

Laser treatment for congenital melanocytic nevi (CMN) is controversial. Correlations between anatomical distribution of facial CMN and efficacy of laser treatment have not been characterized.A total of 90 facial CMN treated with ablative laser (Er:YAG or CO2 laser) were retrospectively reviewed. Clinical assessments were completed by at least two plastic surgeons using the Investigator’s Global Assessment (IGA) score.The mean IGA score was 4.37. The IGA scores recorded at the periorbital, temple/forehead, nose, cheek and lip/chin areas were 3.68, 5.88, 4.63, 4.52 and 4.92, respectively (p = 0.03). Moreover, facial CMN with uniform pigment distribution showed higher IGA scores than those with a non-uniform pigment distribution. Thickening, hairiness and age at first treatment were not statistically correlated with laser efficacy.Correlations between anatomical distribution and the efficacy of laser treatment are described for the first time. The subdivided anatomical distribution of facial CMN can yield meaningful information on predicting the efficacy of laser treatment.

目的 明确静脉/淋巴管畸形的突变基因并进行基因诊断分型.方法 采用二代高通量测序技术,对55例确诊静脉/淋巴管畸形患者的组织样本进行DNA的靶向捕获二代测序和生物信息学分析,对外显子区域和部分内含子区域进行检测,主要检测点突变和插入/缺失突变.结果 55例诊断为静脉/淋巴管畸形患者共采集55个组织样本,经过生物信息学分析和筛选后共发现3种潜在致病基因、15个变异位点,主要突变的基因是TEK和PIK3CA.TEK最常见的突变位点是L914F,单纯TEK突变中86.67％为单纯静脉畸形,100％伴有静脉畸形成分.PIK3CA最常见的突变位点是E542K和E545K.单纯PIK3CA突变中52.63％为血管骨肥大综合征,21.05％为单纯淋巴管畸形,94.74％伴有淋巴管畸形成分.根据基因检测结果,静脉/淋巴管畸形可以分为TEK突变型、PIK3CA突变型、双突变型和无突变型.结论 明确了TEK和PIK3CA是静脉/淋巴管畸形的主要突变基因,据此可将基因分型为TEK突变型、PIK3CA突变型、双突变型和无突变型.基因检测能够预判病灶是否存在静脉畸形或淋巴管畸形成分.

Venous malformation is a common congenital anomaly of vascular development, and endovascular sclerotherapy is currently the first-line treatment for it. Accurate puncture of the lesion is the key to endovascular treatment. Any deviation is likely to result in local ulcers, necrosis and other complications. We described one case, in which a newly developed real-time MRI navigation technology was introduced and sclerotherapy was successfully performed for deep lesions that were difficult to reach by conventional methods. This article reviewed the treatment process of this case, in order to provide guidance and help for venous malformations and other soft tissue diseases in the future.

The restoration of bone defects caused by osteoporosis remains a challenge for surgeons. Strontium ranelate has been applied in preventative treatment approaches due to the biological functions of the trace element strontium (Sr). In this study, we aimed to fabricate bioactive scaffolds through Sr incorporation based on our previously developed modified amino-functional mesoporous bioactive glass (MBG) and to systematically investigate the bioactivity of the resulting scaffold in vitro and in vivo in an osteoporotic rat model. The results suggested that Sr-incorporated amino-functional MBG scaffolds possessed favorable biocompatibility. Moreover, with the incorporation of Sr, osteogenic and angiogenic capacities were upregulated in vitro. The in vivo results showed that the Sr-incorporated amino-functional MBG scaffolds achieved better bone regeneration and vessel formation. Furthermore, bioinformatics analysis indicated that the Sr-incorporated amino-functional MBG scaffolds could reduce reactive oxygen species levels in bone marrow mesenchymal stem cells in the osteoporotic model by activating the cAMP/PKA signaling pathway, thus playing an anti-osteoporosis role while promoting osteogenesis. This study demonstrated the feasibility of incorporating trace elements into scaffolds and provided new insights into biomaterial design for facilitating bone regeneration in the treatment of osteoporosis.

Parthenolide (PTL), a germacrane sesquiterpene lactone extracted from the “Yin” Chinese traditional herb feverfew, has gained interest due to its lethal effects on tumor cells and its pharmacological effects within traditional Chinese medicine theory. To overcome low, non-targeted accumulation and uncontrolled release of PTL administration, a dual-responsive PTL-liposomes@chitosan@gold nanoshells (PTL-Lips@CS@GNS) system was fabricated. Hyperthermia generated under light irradiation in the near-infrared region via local surface plasmon resonance of gold nanoshells induced photothermal therapy, which also stimulated PTL release due to the liposomes gel-to-liquid crystalline phase transition. Additionally, PTL-Lips@CS@GNS exhibited a pH-responsive release in the acidic tumor microenvironment. Collectively, this study provides a realistic strategy for an effective combination of traditional Chinese medicine and current nanotechnology for tumor therapy.

The era of genetics and precision medicine has been reforming this world. How will plastic surgeons in the field of vascular anomalies conform to the trend? This article systematically reviews the identification of serum biomarkers, risk factors, specific mutations in the angiogenesis-related genes such as GNAQ, RASA1, TEK, and their impact on the diagnosis and treatment of vascular anomalies with preliminary results that have been previously reported and leading the tide. Moreover, a new disease classification for complex vascular malformations based on PIK3CA genetic evidence and various treatment breakthroughs is briefly summarized. With gene sequencing, bioinformatics, and big data, we confront the challenges of research in the vascular anomalies domain and explore possibilities of precision medicine development.

目的·评估手术导航系统这一实时立体定向引导技术应用于头颈部危险区域低流量脉管畸形病灶硬化治疗的可行性和安全性.方法·回顾性纳入2017年5月—2019年9月在上海交通大学医学院附属第九人民医院整复外科接受了手术导航系统辅助硬化治疗的头颈部低流量脉管畸形患者.术前将患者计算机断层扫描图像和磁共振图像融合后,进行穿刺路径设计.术中利用导航系统,按预先设计的路径进行穿刺,通过数字减影血管造影验证穿刺结果.统计穿刺成功率和患者术后并发症情况.结果·共纳入10例头颈部低流量脉管畸形患者(6例眼眶内、4例咽部)30处病灶,治疗19次.初次治疗的平均年龄为20.9岁.穿刺成功率达到80.0％(24/30);除1次治疗后患者因硬化剂导致声门溃疡,继而引发肺炎外,未观察到其他并发症.结论·手术导航系统对头颈部危险区域低流量脉管畸形的硬化治疗是可行且安全的辅助技术.

How metabolic status controls the fates of different types of leukemia cells remains elusive. Using a SoNar-transgenic mouse line, we demonstrated that B cell acute lymphoblastic leukemia (B-ALL) cells had a preference in using oxidative phosphorylation. B-ALL cells with a low SoNar ratio (SoNar-low) had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model. The SoNar-low cells were more resistant to cytosine arabinoside (Ara-C) treatment. cyclic adenosine 3',5'-monophosphate response element-binding protein transactivated pyruvate dehydrogenase complex component X and cytidine deaminase to maintain the oxidative phosphorylation level and Ara-C-induced resistance. SoNar-low human primary B-ALL cells also had a preference for oxidative phosphorylation. Suppressing oxidative phosphorylation with several drugs sufficiently attenuated Ara-C-induced resistance. Our study provides a unique angle for understanding the potential connections between metabolism and B-ALL cell fates.

Objectives Functional impairment is a common complaint in patients with venous malformations. Equinus can occur when the venous malformation involves the lower limb, a challenging condition with only a few studies to guide treatment choices. This study was aimed to investigate the operative management of equinus associated with lower limb venous malformations. Method Between August 2015 and September 2017, a total of 12 patients presented with equinus associated with lower limb venous malformations and underwent surgical correction. Preoperative and postoperative clinical symptoms, physical examination and orthopaedic evaluation were retrospectively reviewed. 8 patients who experienced pain underwent percutaneous sclerotherapy prior to the operation. Surgical management included gastrocnemius intramuscular aponeurotic recession, Z-lengthening of the Achilles tendon, Hoke technique and Taylor Spatial Frame external fixation. Results There were eight female and four male patients with a mean age of 14.3 ± 5.9 years. The mean follow-up period was 34.8 ± 9 months. The range of motion of ankle dorsiflexion (with knee extended) improved for each patient (mean, 25.4 degrees; standard deviation, 8.5 degrees). No neurovascular complications were observed. Conclusion Operative correction of equinus associated with lower limb venous malformations is safe and effective. Selective preoperative sclerotherapy is necessary for optimal outcomes.