Radiotherapy-sensitized cancer immunotherapy via cGAS-STING immune pathway by activatable nanocascade reaction.

Radiotherapy-induced immune activation holds great promise for optimizing cancer treatment efficacy. Here, we describe a clinically used radiosensitizer hafnium oxide (HfO2) that was core coated with a MnO2 shell followed by a glucose oxidase (GOx) doping nanoplatform (HfO2@MnO2@GOx, HMG) to trigger ferroptosis adjuvant effects by glutathione depletion and reactive oxygen species production. This ferroptosis cascade potentiation further sensitized radiotherapy by enhancing DNA damage in 4T1 breast cancer tumor cells. The combination of HMG nanoparticles and radiotherapy effectively activated the damaged DNA and Mn2+-mediated cGAS-STING immune pathway in vitro and in vivo. This process had significant inhibitory effects on cancer progression and initiating an anticancer systemic immune response to prevent distant tumor recurrence and achieve long-lasting tumor suppression of both primary and distant tumors. Furthermore, the as-prepared HMG nanoparticles "turned on" spectral computed tomography (CT)/magnetic resonance dual-modality imaging signals, and demonstrated favorable contrast enhancement capabilities activated by under the GSH tumor microenvironment. This result highlighted the potential of nanoparticles as a theranostic nanoplatform for achieving molecular imaging guided tumor radiotherapy sensitization induced by synergistic immunotherapy.

NXPH4 can be used as a biomarker for pan-cancer and promotes colon cancer progression.

NXPH4 promotes cancer proliferation and invasion. However, its specific role and mechanism in cancer remain unclear. Transcriptome and clinical data for pan-cancer were derived from the TCGA database. K-M survival curve and univariate Cox were used for prognostic analysis. CIBERSORT and TIMER algorithms were employed to calculate immune cell infiltration. Gene set enrichment analysis (GSEA) was employed for investigating the function of NXPH4. Western blot verified differential expression of NXPH4 in colon cancer. Functional assays (CCK-8, plate clonogenicity assay, wound healing assay, and Transwell assay) confirmed the impact of NXPH4 on proliferation, invasion, and migration of colon cancer cells. Dysregulation of NXPH4 in pan-cancer suggests its potential as a diagnostic and prognostic marker for certain cancers, including colon and liver cancer. High expression of NXPH4 in pan-cancer might be associated with the increase in copy number and hypomethylation. NXPH4 expression in pan-cancer is substantially linked to immune cell infiltration in the immune microenvironment. NXPH4 expression is associated with the susceptibility to immunotherapy and chemotherapy. Western blot further confirmed the higher expression of NXPH4 in colon cancer. Knockdown of NXPH4 significantly suppresses proliferation, invasion, and migration of colon cancer cell lines HT-29 and HCT116, as validated by functional assays.

Intermittent administration of PTH for the treatment of inflammatory bone loss does not enhance entheseal pathological new bone formation.

OBJECTIVE: To investigate the effect of intermittent parathyroid hormone (iPTH) administration on pathological new bone formation during treatment of ankylosing spondylitis-related osteoporosis. METHODS: Animal models with pathological bone formation caused by hypothetical AS pathogenesis received treatment with iPTH. We determined the effects of iPTH on bone loss and the formation of pathological new bone with micro-computed tomography (micro-CT) and histological examination. In addition, the tamoxifen-inducible conditional knockout mice (CAGGCre-ERTM; PTHflox/flox, PTH-/-) was established to delete PTH and investigate the effect of endogenous PTH on pathological new bone formation. RESULTS: iPTH treatment significantly improved trabecular bone mass in the modified collagen-induced arthritis (m-CIA) model and unbalanced mechanical loading models. Meanwhile, iPTH treatment did not enhance pathological new bone formation in all types of animal models. Endogenous PTH deficiency had no effects on pathological new bone formation in unbalanced mechanical loading models. CONCLUSION: Experimental animal models of AS treated with iPTH show improvement in trabecular bone density, but not entheseal pathological bone formation，indicating it may be a potential treatment for inflammatory bone loss does in AS.

Design and analysis of unequal aperture off-axis optical integrator for solar simulators.

The unequal aperture off-axis optical integrator design method is proposed to improve the irradiation uniformity of solar simulators and solve the problem of limited uniformity of optical integrator due to aberrations and uneven distribution of incident radiation. Firstly, the unequal aperture off-axis optical integrator structure is designed based on the scalar diffraction theory to analyze the factors affecting the optical homogenization ability of the optical integrator. Then, the relationship between sub-eye lens aperture and arrangement is explored in combination with Lagrange invariance principle and semi-definite programming theory. Finally, the optimum off-axis amount of sub-eye lens with different ring band is determined from the perspective of geometric optics by using the aberration theory and following the principle of edge light, so as to improve the evenness of optical integrator. The design results are verified by the simulation analysis. The simulation results show that: In the picture plane of optical integrator, the irradiation non-uniformity in the ф 26 mm irradiation plane is 14.87%, which is better than 26.02% in the traditional optical integrator. At the same time, at the effective irradiated surface, the irradiation non-uniformity of 0.53% within the ф 300 mm reaches the irradiation standard of the class A + solar simulator, and the irradiance only decreases by 16.5% compared with the traditional optical integrator, which still meets the index requirement of a solar constant. The goal of improving the evenness of optical integrator is realized without greatly affecting irradiance and without introducing aspherical design.

Cancer Radiosensitization Nanoagent to Activate cGAS-STING Pathway for Molecular Imaging Guided Synergistic Radio/Chemo/Immunotherapy.

Immunotherapy has emerged as an innovative strategy with the potential to improve outcomes in cancer patients. Recent evidence indicates that radiation-induced DNA damage can activate the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to enhance the antitumor immune response. Even so, only a small fraction of patients currently benefits from radioimmunotherapy due to the radioresistance and the inadequate activation of the cGAS-STING pathway. Herein, this work integrates hafnium oxide (HfO2 ) nanoparticles (radiosensitizer) and 7-Ethyl-10-hydroxycamptothecin (SN38, chemotherapy drug, STING agonist) into a polydopamine (PDA)-coated core-shell nanoplatform (HfO2 @PDA/Fe/SN38) to achieve synergistic chemoradiotherapy and immunotherapy. The co-delivery of HfO2 /SN38 greatly enhances radiotherapy efficacy by effectively activating the cGAS-STING pathway, which then triggers dendritic cells maturation and CD8+ T cells recruitment. Consequently, the growth of both primary and abscopal tumors in tumor-bearing mice is efficiently inhibited. Moreover, the HfO2 @PDA/Fe/SN38 complexes exhibit favorable magnetic resonance imaging (MRI)/photoacoustic (PA) bimodal molecular imaging properties. In summary, these developed multifunctional complexes have the potential to intensify immune activation to realize simultaneous cancer Radio/Chemo/Immunotherapy for clinical translation.

Tenascin-C promotes endochondral ossification and fracture healing through Hedgehog and Hippo signaling.

Fractures are frequent and severe musculoskeletal injuries. This study aimed to investigate the function of tenascin-C (TNC) in regulating chondrogenic during fracture healing and elucidate the underlying molecular mechanisms. A well-established femur fracture model in male C57BL/6J mice was used to transect the middle diaphysis of the femur. To identify the essential role of TNC, shTNC lentiviruses or TNC protein were administered in the animal model. Micro-CT analysis, histologic analysis, immunostaining assays, and gene expression analysis were employed to investigate the effect of TNC during fracture healing. An in vitro mesenchymal stem cell culture system was developed to investigate the role and molecular mechanism of TNC in regulating chondrogenesis. TNC expression was induced at the inflammatory phase and peaked at the cartilaginous callus phase during fracture healing. Knockdown of TNC expression in callus results in decreased callus formation and impaired fracture healing. Conversely, administration of exogenous TNC promoted chondrogenic differentiation, cartilage template formation and ultimately improved fracture healing. Both the Hedgehog and Hippo signaling pathways were found to be involved in the pro-chondrogenic function of TNC. Our observations demonstrate that TNC is a crucial factor responsible for endochondral ossification in fracture healing and provide a potential therapeutic strategy for promoting fracture healing.

Response of a submerged macrophyte (Vallisneria natans) to water depth gradients and sediment nutrient concentrations.

Submerged plants constitute a vital component of shallow lake ecosystems, where water depth and sediment nitrogen­phosphorus content are two key factors influencing their growth. This study focuses on Vallisneria natans and investigates the morphological and physiological changes of V. natans under the interaction of three water depth gradients and two different sediment nutrient levels. It explores the mechanisms through which varying sediment nutrient conditions under different water depths affect the growth of V. natans. The results indicate that both independent and interactive effects of water depth and sediment nutrient status significantly impact the morphology, antioxidant enzyme activity, and photosynthetic pigment content of V. natans, with water depth having a greater influence. To adapt to increased water depth-induced light stress, V. natans responds morphologically by increasing leaf length, leaf width, and decreasing maximum root length. Physiologically, it enhances its antioxidant regulation capacity and photosynthetic efficiency by increasing antioxidant enzyme activity, root vitality, and photosynthetic pigment content to counter weak light stress. However, these adaptations are insufficient to cope with excessively deep waters (200 cm). Sediment nutrient levels primarily control the growth of V. natans by affecting its root system. When sediment nitrogen and phosphorus content is lower, V. natans exhibits greater total root volume and surface area to enhance nutrient absorption efficiency. Water depth not only directly influences the growth of submerged plants but may also impact the migration and transformation of phosphorus in sediments, further exacerbating its effects on the growth of these plants, thus accelerating the regime shift of shallow lakes. Therefore, this study reveals V. natans' response strategies to varying water depths and sediment nutrient levels, determining suitable water levels and sediment nutrient conditions for its growth. These research findings provide a scientific basis for water level management and ecological restoration of submerged aquatic plants in shallow lakes.

Functionalized TMC and ε-CL elastomers with shape memory and self-healing properties.

Introduction: Smart elastomers, which possess self-healing and shape memory capabilities, have immense potential in the field of biomedical applications. Polycarbonates and polyesters have gained widespread interest due to their remarkable biocompatibility over the last century. Nevertheless, the lack of functional versatility in conventional polyesters and polycarbonates means that they fall short of meeting the ever-evolving demands of the future. Methods: This paper introduced a new smart elastomer, named mPEG43-b-(PMBC-co-PCL)n, developed from polyester and polycarbonate blends, that possessed shape memory and self-heal capabilities via a physical crosslinking system. Results: The material demonstrated a significant tensile strength of 0.38 MPa and a tensile ratio of 1155.6%, highlighting its favorable mechanical properties. In addition, a conspicuous shape retrieval rate of 93% was showcased within 32.5 seconds at 37°C. Remarkably, the affected area could be repaired proficiently with no irritation experienced during 6h at room temperature, which was indicative of an admirable repair percentage of 87.6%. Furthermore, these features could be precisely modified by altering the proportion of MBC and ε-CL to suit individual constraints. Discussion: This innovative elastomer with exceptional shape memory and self-heal capabilities provides a solid basis and promising potential for the development of self-contracting intelligent surgical sutures in the biomedical field.

Association between cognitive impairment and olfactory deficits in systemic lupus erythematosus without major neuropsychiatric syndromes.

OBJECTIVE: The aim of the study was to investigate the utility of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), evaluate cognitive deficits in systemic lupus erythematosus (SLE) patients and examine the relationship between cognitive and olfactory functions. METHODS: 55 SLE patients and 50 healthy controls were administered by RBANS including five indexes: immediate memory (IMME), visuospatial/constructional (Vis/Con), language (LANG), attention (ATT), and delayed memory (DEME). Olfactory functions were evaluated by computerized testing including three stages of smell: threshold (THR), identification (ID), and memory (ME) of different odors. The disease activity and cumulative damage were assessed by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI). RESULTS: SLE patients exhibited significant lower total RBANS scores, IMME, Vis/Con, ATT, and DEME index scores than healthy controls (p < 0.01 for all and p = 0.027 for attention). Reduced RBANS scores were associated with several organ involvement and autoantibodies. SLE patients with higher SLEDAI-2K scores or with accumulated damage (SDI≥1) showed decreased RBANS scores. All the olfactory scores in SLE patients were significantly decreased than controls (p = 0.001). Patients had higher proportion of anosmia (8.57% vs 0%) and hyposmia (28.58% vs 5.72%) than controls (χ2 = 10.533, p = 0.015). Multivariable regression analysis revealed that olfactory functions had a positive effect on RBANS index scores. Olfactory memory and total scores were significantly correlated with the DEME (r = 0.393, p = 0.021) and total scores (r = 0.429, p = 0.011). CONCLUSION: This study indicates that significantly cognitive and olfactory functions are impaired in SLE patients. The RBANS is a potentially useful instrument for evaluating neuropsychological status in SLE. Physicians are encouraged to perform routine screening in SLE patients to detect subtle cognitive dysfunction.

Estimation and potential ecological risk assessment of multiphase PAEs in mangrove wetlands in Dongzhai Harbor, Hainan.

With the application of plastic products, phthalates now widely occur in various environmental media. A large number of ecological risk assessment experiments have only been carried out on a single medium such as water or sediment. There are few reports of ecological risk assessments based on the phase states of phthalic acid esters (PAEs) such as the free dissolved state and the dissolved organic carbon (DOC) adsorption state. In this study, the concentrations of the free dissolved state, the DOC adsorption state, and the easily released PAEs in the sediments, as well as the dissolved organic carbon release potential and their influencing factors were calculated in the Dongzhaigang water body. The potential ecological risks posed by state-of-the-art PAEs were investigated. The average concentration of six freely dissolved PAEs in water was 0.542 (0.226-1.115) µg/L, accounting for 76.3 % of the total PAEs. The PAEs with the highest concentrations in the free dissolved state were di-n-butyl phthalate (DBP, 0.383 µg/L), followed by Di(2-ethylhexyl) phthalate (DEHP, 0.094 µg/L). The average concentration of all six PAEs (∑6PAEs) adsorbed by the DOC in the water was 0.172 µg/L, accounting for 23.74 % of all of the PAEs. The DOC-adsorbed DEHP (0.148 µg/L) accounted for about 86 % of the six adsorbed PAEs. Sediment organic carbon may affect the release potential of the DOC through changing the soluble organic carbon concentration. Most types of PAEs in water posed low risk to organisms. However, DBP posed low and medium risk to algae and crustaceans, and medium risk to fish. Medium or high risk of DEHP to algae, crustaceans and fish was observed. The high ecological risk of PAEs related to sediments were only found at S13 and S14. Generally, the potential ecological risk of PAEs in sediment was more stable than that in water bodies.

Variation in the concentration of particulate Pd in the Nandu River Estuary during spring-neap tides.

Estuaries are environmental systems with great resource potential and environmental benefits. This study investigates the role of particulate palladium (Pd) in the Nandu River Estuary in the enrichment of estuarine geochemical processes during spring-neap tides. Particulate Pd was found to show different characteristics during spring-neap tides, with the hydrodynamic condition being one of the key factors causing the difference. In addition, particulate Pd showed a decreasing trend while moving from the mouth to the upstream. The highest value of particulate Pd was 35.32 ng L-1, which occurred at the intersection of the mainstream and the branch during the neap tide, and the lowest value was 0.86 ng·L-1, which occurred in the far mouth area during the spring tide. The concentrations of particulate Pd during the neap and spring tides were 5.53 (1.01-35.32) ng·L-1 and 2.33 (0.86-5.22) ng·L-1, respectively. With the exception of stations 1, 5, 10, 11, and 15, the concentration of particulate Pd during the neap tide was greater than that during the spring tide. The variation in the particulate Pd was inconsistent between the spring tide and the neap tide, and the fluctuation in each study section during the neap tide was greater than that during the spring tide. In addition, since the emissions from catalytic converter are in the form of nanoparticles, they are difficult to be dissolve in natural water, and therefore, the concentration of particulate Pd was obviously greater in the waters near large bridges and main roads. An analysis of the physical and chemical properties of the water showed that Cl- easily combined with dissolved Pd and was one of the important factors that affected the concentration of particulate Pd. In addition, DO and Eh had little effect on the change in the particulate Pd during the tidal cycle, and pH had a significant positive correlation with particulate Pd.

Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation in ankylosing spondylitis.

OBJECTIVE: The aim of this study was to identify the role of Piezo1-mediated mechanotransduction in entheseal pathological new bone formation and to explore the underlying molecular mechanism. METHODS: Spinal ligament tissues were collected from 14 patients with ankylosing spondylitis (AS) and 14 non-AS controls and bulk RNA sequencing was conducted. Collagen antibody-induced arthritis models were established to observe pathological new bone formation. Pharmacological inhibition and genetic ablation of Piezo1 was performed in animal models to identify the essential role of Piezo1. Entheseal osteo-chondral lineage cells were collected and in vitro cell culture system was established to study the role and underlying mechanism of Piezo1 in regulation of chondrogenesis, osteogenesis and its own expression. RESULTS: Piezo1 was aberrantly upregulated in ligaments and entheseal tissues from patients with AS and animal models. Pharmaceutical and genetic inhibition of Piezo1 attenuated while activation of Piezo1 promoted pathological new bone formation. Mechanistically, activation of CaMKII (Calcium/calmodulin dependent protein kinase II) signalling was found essential for Piezo1-mediated mechanotransduction. In addition, Piezo1 was upregulated by AS-associated inflammatory cytokines. CONCLUSION: Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation through CaMKII signalling in AS.

Optical design of a solar simulator for meteorological fields to improve irradiance uniformity and expand the range of irradiation regulation.

Aiming at the problems of low irradiation uniformity and a narrow irradiance regulation range in the existing solar simulators, an optical design method for meteorological solar simulators with high irradiation uniformity and wide-range irradiance is proposed. Using a xenon lamp and a variable coefficient non-coaxial ellipsoid reflector as the concentrator system, we analyze the causes of stray light in the optical integrator. The optimal design method of the integrator based on the anti-crosstalk diaphragm and the light propagation matrix model, which effectively suppress the stray light, is proposed. The irradiance regulation system is designed to continuously regulate the irradiance in a wide range. The optimal design method of the collimated system is given. The rationality of the system design is verified by the simulation of LightTools software. The results show that within the effective irradiation surface of 100mm×100mm, the irradiance is continuously adjustable in the range of 100-1400W/m2, and the irradiation uniformity is better than 99.10% under different irradiances. This research breaks through the limitations of low irradiation uniformity and a narrow irradiance adjustment range of traditional meteorological solar simulators and can provide accurate and reliable solar irradiance for the verification and calibration of pyranometers.

Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis.

Non-small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide. A growing number of studies have suggested that long noncoding RNAs (lncRNAs) play a key role in the progression of non-small cell lung cancer (NSCLC). Here, we report a novel lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) that exhibits oncogenic properties in NSCLC. The lncRNA DLGAP1-AS1 and denticleless protein homolog (DTL) presented upregulated expression, but microRNA-193a-5p (miR-193a-5p) showed downregulated expression in cancerous tissues of human lung samples from 48 patients with NSCLC. Partial loss of lncRNA DLGAP1-AS1 reduced malignant cell viability, migration, and invasion but induced apoptosis. Dual-luciferase reporter gene, RNA pull-down and RNA binding protein immunoprecipitation assays demonstrated enrichment of lncRNA DLGAP1-AS1 in miR-193a-5p and Argonaute 2, suggesting that lncRNA DLGAP1-AS1 modulated DTL, a putative target of miR-193a-5p. We also found that restoration of miR-193a-5p rescued NSCLC cell biological functions affected by overexpression of lncRNA DLGAP1-AS1. Silencing lncRNA DLGAP1-AS1 was found to reduce the tumorigenesis of NSCLC cells xenografted into nude mice, which was rescued by DTL overexpression. In conclusion, our study highlights a novel regulatory network of the lncRNA DLGAP1-AS1/miR-193a-5p/DTL axis in NSCLC, providing a potential therapeutic strategy for NSCLC.

Hyaluronic acid-based nano drug delivery systems for breast cancer treatment: Recent advances.

Breast cancer (BC) is the most common malignancy among females worldwide, and high resistance to drugs and metastasis rates are the leading causes of death in BC patients. Releasing anti-cancer drugs precisely to the tumor site can improve the efficacy and reduce the side effects on the body. Natural polymers are attracting extensive interest as drug carriers in treating breast cancer. Hyaluronic acid (HA) is a natural polysaccharide with excellent biocompatibility, biodegradability, and non-immunogenicity and is a significant component of the extracellular matrix. The CD44 receptor of HA is overexpressed in breast cancer cells and can be targeted to breast tumors. Therefore, many researchers have developed nano drug delivery systems (NDDS) based on the CD44 receptor tumor-targeting properties of HA. This review examines the application of HA in NDDSs for breast cancer in recent years. Based on the structural composition of NDDSs, they are divided into HA NDDSs, Modified HA NDDSs, and HA hybrid NDDSs.

Genomic Alteration Spectrum of Non-Small Cell Lung Cancer Patients in East-China Characterized by Tumor Tissue DNA and Cell-Free DNA.

Introduction: From an oncologic perspective, genetic detection is becoming a frontline clinical test, used to identify actionable alterations for targeted therapy, monitor molecular clonal tumor evolution, indicate disease progression and prognosis, and predict medication efficacy and resistance. From analysis of both tumor tissue and cell-free DNA from a large cohort of non-small cell lung cancer patients in East-China, we characterized the full spectrum of genomic alterations. Methods: The study comprised 3000 unpaired samples including 1351 tumor tissue DNA (tDNA) and 1649 cell-free circulating tumor DNA (cfDNA) samples, from which 67 cancer-related genes were sequenced and the genetic alteration profiles were depicted. Integrative molecular analyses identified the frequently mutated genes, uncovered co-occurring somatic alterations, described the distribution of hotspot variants, analyzed the frequency of variant alleles, and notably distinguished actionable, novel variants. Results: The most commonly affected genes were EGFR, TP53, KRAS, CDKN2A, and PIK3CA in both tDNA and cfDNA samples. EGFR and CTNNB1, PIK3CA and PTEN, ERBB2 and SMO were found to have frequent co-occurring alterations in tDNA samples, while EGFR and SMO, KRAS and PDGFRA, PIK3CA and KDR were in cfDNA samples. A large number of primary druggable variants were identified in tDNA samples, while numerous drug-resistance variants, rare actionable variants, and non-EGFR actionable variants were detected in cfDNA samples. Novel variants were enriched in KDR, KIT, TP53, ABL1, FGFR1 in tDNA samples while the majority of novel variants were distributed in PDGFRA, EGFR, KIT, ROS1, BRCA2 in cfDNA samples. Variant allele frequency in tDNA samples was significantly (P < 0.001) higher than that in cfDNA samples. Conclusion: The results revealed considerable differences in the alteration characteristics between the two kinds of specimens. To date, this study represents the largest real-world investigation of its kind, derived from the largest number of patients in East-China. It reinforced and expanded the mechanism of molecular analysis of neoplastic genetic profiles.

Dual nanoenzymes loaded hollow mesoporous organotantalum nanospheres for chemo-radio sensitization.

Chemo-radiotherapy has been extensively used in clinics, displaying substantial advantages in treatment and prognosis. Stimuli-responsive biodegradable nanoagents that can achieve not only delivery and controlled release of chemotherapeutics, but also hypoxia alleviation to enhance chemoradiotherapy therefore has tremendous potential. Herein, glutathione (GSH)-responsive, biodegradable, doxorubicin-carrying hollow mesoporous organotantalum nanospheres modified with Au and Pt dual nanoenzymes (HMOTP@Pt@Au@Dox) were constructed for chemo-radio sensitization. Degradation of HMOTP@Pt@Au@Dox can be self-activated through GSH stimulation and on-demand release packaged Dox owing to the disulfide bond in the hybrid framework of organotantalum nanospheres. Au and Pt nanoenzymes triggered cascade catalytic reactions that could alleviate hypoxia by utilizing ß-d-glucose and H2O2, thereby sensitizing ROS-based chemoradiotherapy with synergistic starving therapy. Given the radiosensitization of high-Z elements (Ta, Pt, Au), nanoenzymes induced cascade catalytic reaction for hypoxia relief, and the depletion of the predominant antioxidant GSH, desirable tumor suppression could be achieved both in vitro and in vivo, indicating that HMOTP@Pt@Au@Dox is a promising nanoagent to boost chemo-radiotherapy.

CXCL12/CXCR4-Rac1-mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by inflammatory back pain and spinal ankylosis due to pathological new bone formation. Here, we identified CXCL12 as a critical contributor to pathological new bone formation through recruitment of osteogenic precursor cells (OPCs). CXCL12 was found highly expressed in the regions that would potentially develop pathological new bone. OPCs were recruited to the regions where CXCL12 was up-regulated. Inhibition of CXCL12/CXCR4 axis with AMD3100 or conditional knockout of CXCR4 attenuated OPCs migration and subsequent pathological new bone formation in animal models of AS. By contrast, a genetically engineered animal model with CXCL12 overexpression developed a joint ankylosis phenotype. Furthermore, Rac1 was found essential for OPCs migration and pathological new bone formation. These findings ravel the novel role of CXCL12 in AS and indicate a potential strategy for targeting the CXCL12/CXCR4-Rac1 axis to prevent progression of axial skeleton ankylosis.