IL-11-Engineered Macrophage Membrane-Coated Reactive Oxygen Species-Responsive Nanoparticles for Targeted Delivery of Doxorubicin to Osteosarcoma.

Osteosarcoma (OS) is a lethal malignant orthotopic bone tumor that primarily affects children and adolescents. Biomimetic nanocarriers have attracted wide attention as a new strategy for delivering chemotherapy agents to the OS. However, challenges such as rapid clearance and limited targeting hinder the effectiveness of OS chemotherapy. In this study, we designed reactive oxygen species (ROS)-responsive nanoparticles (NPs) coated with an interleukin (IL)11-engineered macrophage membrane (MM). The camouflage by MMs prevents clearance of IL-11-engineered MM-coated NPs loaded with doxorubicin (IL-11/MM@NPs/Dox) by the immune system. Moreover, the macrophage membrane combined with surface-expressed IL-11 not only directed IL-11/MM@NPs/Dox to OS tissues but also selectively identified IL-11 receptor alpha (IL-11Rα)-enriched OS cells. Within these cells, elevated levels of ROS triggered the controlled release of Dox from the ROS-responsive NPs. The synergistic modification of targeted ligand conjugation and cell membrane coating on the ROS-responsive NPs enhanced drug availability and reduced toxic side effects, thereby boosting the efficacy of OS chemotherapy. In summary, our findings suggest that IL-11/MM@NPs/Dox represents a promising approach to improving OS chemotherapy efficacy while ensuring excellent biocompatibility.

Modified Standard Total en bloc Spondylectomy for Solitary Thoracic or Lumbar Spinal Metastasis: A 1-Stage Posterior Approach Under Direct Visualization.

BACKGROUND: Solitary spinal metastasis (SM) is one of the indications for total en bloc spondylectomy (TES). Conventional TES carries the risk of damage to the great vessels anterior to the vertebral column, mainly because of a lack of visualization of the anterior structures. In this study, we devised a modified standard TES technique to achieve direct visualization in a 1-stage posterior approach. METHODS: Included in this study were patients ≥18 years old with solitary thoracic or lumbar SM who underwent the modified standard TES at our institution between January 2017 and October 2022. Patient data were retrospectively sourced from medical records, and patients had a minimum of 3 months of postoperative follow-up. RESULTS: This study involved 71 East Asian patients (median age, 57 years; 34 males), comprising 38 patients with thoracic SM and 33 with lumbar SM. Lung cancer was the most common tumor histology. Fourteen patients (19.7%) experienced intraoperative complications; pleural rupture was the predominant complication, and there were no cases of injury to the spinal cord or great vessels. The median operative time was 305 minutes (range, 203 to 660 minutes). The median intraoperative blood loss was 1,000 mL (range, 400 to 4,000 mL). The median perioperative blood transfusion was 4 units (range, 0 to 12 units), and the median hospitalization duration was 17 days (range, 14 to 29 days). Additionally, 27 patients (38.0%) had acute (perioperative) complications. Seven patients were lost to follow-up. Significant clinical improvement was achieved 3 months postoperatively. Postoperative early and late complications were observed in 5 patients. Of the 64 patients with completed follow-up, 47 (73.4%) had negative surgical margins, and none received postoperative radiation therapy. Revision surgery for local tumor recurrence was performed in 4.7% of patients. The median follow-up was 31.5 months (range, 3 to 81 months). CONCLUSIONS: Our modified standard TES was demonstrated to be a safe and effective surgical technique for solitary thoracolumbar SM. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Comparisons of clinical characteristics, treatments, and outcomes among different pathological subtypes of chondrosarcoma in the spine.

INTRODUCTION: Spinal chondrosarcoma exhibits higher invasiveness and a worse prognosis compared to chondrosarcoma in the extremities. The prognosis and therapeutic plan vary greatly among different pathological subtypes of chondrosarcoma. This study aimed to analyze the differences in clinical characteristics, molecular features, therapeutic effects, and prognostic factors among the subtypes of chondrosarcoma in the spine. METHODS: A retrospective review was conducted on 205 patients with spinal chondrosarcoma. The clinical features and immunohistochemical (IHC) markers were compared among the pathological subtypes of chondrosarcoma grade 1, grade 2, grade 3, mesenchymal chondrosarcoma (MCS), dedifferentiated chondrosarcoma (DCS), and clear cell chondrosarcoma (CCCS). Chondrosarcoma grade 1/2/3 are collectively referred to as conventional chondrosarcoma (CCS) for multivariate survival analysis. Univariate and multivariate analyses were performed to investigate independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS) in patients with spinal chondrosarcoma. Furthermore, independent prognostic factors for OS and RFS were identified in CCS and MCS. RESULTS: MCS patients were younger than the other subtypes. Patients with chondrosarcoma grade 1/2 had better OS than those with chondrosarcoma grade 3, MCS and DCS, while only chondrosarcoma grade 1 patients showed better RFS than chondrosarcoma grade 2/3, MCS and DCS patients. Ki-67 index was higher in chondrosarcoma grade 3, MCS and DCS than chondrosarcoma grade 1/2. The comparison of IHC markers further highlighted the overexpression of P53/MDM2 in MCS and DCS. Gross total resection, including en-bloc and piecemeal resection, significantly improved OS and RFS for CCS patients, while only en-bloc resection significantly improved the prognosis of MCS patients. Chemotherapy appeared to be important for the OS of MCS patients. CONCLUSION: P53/MDM2 pathway was upregulated in MCS and DCS compared to chondrosarcoma grade 1/2. Radical tumor resection is crucial for the treatment of spinal chondrosarcoma, while MCS patients require further comprehensive treatments perioperatively.

Remote neurostimulation through an endogenous ion channel using a near-infrared light-activatable nanoagonist.

The development of noninvasive approaches to precisely control neural activity in mammals is highly desirable. Here, we used the ion channel transient receptor potential ankyrin-repeat 1 (TRPA1) as a proof of principle, demonstrating remote near-infrared (NIR) activation of endogenous neuronal channels in mice through an engineered nanoagonist. This achievement enables specific neurostimulation in nongenetically modified mice. Initially, target-based screening identified flavins as photopharmacological agonists, allowing for the photoactivation of TRPA1 in sensory neurons upon ultraviolet A/blue light illumination. Subsequently, upconversion nanoparticles (UCNPs) were customized with an emission spectrum aligned to flavin absorption and conjugated with flavin adenine dinucleotide, creating a nanoagonist capable of NIR activation of TRPA1. Following the intrathecal injection of the nanoagonist, noninvasive NIR stimulation allows precise bidirectional control of nociception in mice through remote activation of spinal TRPA1. This study demonstrates a noninvasive NIR neurostimulation method with the potential for adaptation to various endogenous ion channels and neural processes by combining photochemical toolboxes with customized UCNPs.

Regulation of ferroptosis by nanotechnology for enhanced cancer immunotherapy.

INTRODUCTION: This review explores the innovative intersection of ferroptosis, a form of iron-dependent cell death, with cancer immunotherapy. Traditional cancer treatments face limitations in efficacy and specificity. Ferroptosis as a new paradigm in cancer biology, targets metabolic peculiarities of cancer cells and may potentially overcome such limitations, enhancing immunotherapy. AREA COVERED: This review centers on the regulation of ferroptosis by nanotechnology to augment immunotherapy. It explores how nanoparticle-modulated ferroptotic cancer cells impact the TME and immune responses. The dual role of nanoparticles in modulating immune response through ferroptosis are also discussed. Additionally, it investigates how nanoparticles can be integrated with various immunotherapeutic strategies, to optimize ferroptosis induction and cancer treatment efficacy. The literature search was conducted using PubMed and Google Scholar, covering articles published up to March 2024. EXPERT OPINION: The manuscript underscores the promising yet intricate landscape of ferroptosis in immunotherapy. It emphasizes the need for a nuanced understanding of ferroptosis' impact on immune cells and the TME to develop more effective cancer treatments, highlighting the potential of nanoparticles in enhancing the efficacy of ferroptosis and immunotherapy. It calls for deeper exploration into the molecular mechanisms and clinical potential of ferroptosis to fully harness its therapeutic benefits in immunotherapy.

The role of LOXL2 in tumor progression, immune response and cellular senescence: a comprehensive analysis.

LOXL2, an enzyme belonging to the LOX family, facilitates the cross-linking of extracellular matrix (ECM) elements. However, the roles of the LOXL2 gene in mechanisms of oncogenesis and tumor development have not been clearly defined. In this pan-cancer study, we examined the notable disparity in LOXL2 expression at the mRNA and protein levels among various cancer types and elucidated its interconnected roles in tumor progression, mutational profile, immune response, and cellular senescence. Apart from investigating the hyperexpression of LOXL2 being related to poorer prognosis in different types of tumors, this study also unveiled noteworthy connections between LOXL2 and genetic mutations, infiltration of tumor immune cells, and genes in immune checkpoint pathways. Further analysis revealed the participation of LOXL2 in multiple pathways related to cancer extracellular matrix remodeling and cellular senescence. Moreover, our investigation uncovered that the knockdown and inhibition of LOXL2 significantly attenuated the proliferation and migration of PC-9 and HCC-LM3 cells. The knock-down and inhibition of LOXL2 enhanced cellular senescence in lung and liver cancer cells, as confirmed by SA-ß-Gal staining and quantitative RT-PCR analyses. This comprehensive analysis offers valuable insights on the functions of LOXL2 in different types of cancer and its role in regulating the senescence of cancer cells.

Risks for prolonged mechanical ventilation and reintubation after cervical malignant tumor surgery: a nested case-control study.

PURPOSE: Prolonged mechanical ventilation (PMV) and reintubation are among the most serious postoperative adverse events associated with malignant cervical tumors. In this study, we aimed to clarify the incidence, characteristics, and risk factors for PMV and reintubation in target patients. METHODS: This retrospective nested case-control study was performed between January 2014 and January 2020 at a large spinal tumor center in China. Univariate analysis was used to identify the possible risk factors associated with PMV and reintubation. Logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) with covariates of a probability < 0.05 in univariate analysis. RESULTS: From a cohort of 560 patients with primary malignant (n = 352) and metastatic (n = 208) cervical tumors, 27 patients required PMV and 20 patients underwent reintubation. The incidence rates of PMV and reintubation were 4.82% and 3.57%, respectively. Three variables (all p < 0.05) were independently associated with an increased risk of PMV: Karnofsky Performance Status < 50 compared to ≥ 80, operation duration ≥ 8 h compared to < 6 h, and C4 nerve root encased by the tumor. Longer operative duration and preoperative hypercapnia (all p < 0.05) were independent risk factors for postoperative reintubation, both of which led to longer length of stay (32.6 ± 30.8 vs. 10.7 ± 5.95 days, p < 0.001), with an in-hospital mortality of 17.0%. CONCLUSION: Our results demonstrate the risk factors for PMV or reintubation after surgery for malignant cervical tumors. Adequate assessment, early detection, and prevention are necessary for this high-risk population.

miR-1246 promotes osteosarcoma cell migration via NamiRNA-enhancer network dependent on Argonaute 2.

High metastatic propensity of osteosarcoma leads to its therapeutic failure and poor prognosis. Although nuclear activation miRNAs (NamiRNAs) are reported to activate gene transcription via targeting enhancer and further promote tumor metastasis, it remains uncertain whether NamiRNAs regulate osteosarcoma metastasis and their exact mechanism. Here, we found that extracellular vesicles of the malignant osteosarcoma cells (143B) remarkably increased the migratory abilities of MNNG cells representing the benign osteosarcoma cells by two folds, which attributed to their high miR-1246 levels. Specially, miR-1246 located in nucleus could activate the migration gene expression (such as MMP1) to accelerate MNNG cell migration through elevating the enhancer activities via increasing H3K27ac enrichment. Instead, MMP1 expression was dramatically inhibited after Argonaute 2 (AGO2) knockdown. Notably, in vitro assays demonstrated that AGO2 recognized the hybrids of miR-1246 and its enhancer DNA via PAZ domains to prevent their degradation from RNase H and these protective roles of AGO2 may favor the gene activation by miR-1246 in vivo. Collectively, our findings suggest that miR-1246 could facilitate osteosarcoma metastasis through interacting with enhancer to activate gene expression dependent on AGO2, highlighting the nuclear AGO2 as a guardian for NamiRNA-targeted gene activation and the potential of miR-1246 for osteosarcoma metastasis therapy.

MOCS, a novel classifier system integrated multimoics analysis refining molecular subtypes and prognosis for skin melanoma.

PURPOSE: The present investigation focuses on Skin Cutaneous Melanoma (SKCM), a melanocytic carcinoma characterized by marked aggression, significant heterogeneity, and a complex etiological background, factors which collectively contribute to the challenge in prognostic determinations. We defined a novel classifier system specifically tailored for SKCM based on multiomics. METHODS: We collected 423 SKCM samples with multi omics datasets to perform a consensus cluster analysis using 10 machine learning algorithms and verified in 2 independent cohorts. Clinical features, biological characteristics, immune infiltration pattern, therapeutic response and mutation landscape were compared between subtypes. RESULTS: Based on consensus clustering algorithms, we identified two Multi-Omics-Based-Cancer-Subtypes (MOCS) in SKCM in TCGA project and validated in GSE19234 and GSE65904 cohorts. MOCS2 emerged as a subtype with poor prognosis, characterized by a complex immune microenvironment, dysfunctional anti-tumor immune state, high cancer stemness index, and genomic instability. MOCS2 exhibited resistance to chemotherapy agents like erlotinib and sunitinib while sensitive to rapamycin, NSC87877, MG132, and FH355. Additionally, ELSPBP1 was identified as the target involving in glycolysis and M2 macrophage infiltration in SKCM. CONCLUSIONS: MOCS classification could stably predict prognosis of SKCM; patients with a high cancer stemness index combined with genomic instability may be predisposed to an immune exhaustion state.Communicated by Ramaswamy H. Sarma.

Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.

Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts, indicating that Src function is essential in osteoclasts. G-protein-coupled receptors (GPCRs) are the targets for ∼35% of approved drugs but it is still unclear how GPCRs regulate Src kinase activity. Here, we reveal that GPR54 activation by its natural ligand Kisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus. We show that Kp-10 binding to Gpr54 leads to the up-regulation of Dusp18. Kiss1, Gpr54 and Dusp18 knockout mice all exhibit osteoclast hyperactivation and bone loss, and Kp-10 abrogated bone loss by suppressing osteoclast activity in vivo. Therefore, Kp-10/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation.

Identification and Verification of Novel Biomarkers Involving Rheumatoid Arthritis with Multimachine Learning Algorithms: An In Silicon and In Vivo Study.

Background: Rheumatoid arthritis (RA) remains one of the most prevalent chronic joint diseases. However, due to the heterogeneity among RA patients, there are still no robust diagnostic and therapeutic biomarkers for the diagnosis and treatment of RA. Methods: We retrieved RA-related and pan-cancer information datasets from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. Six gene expression profiles and corresponding clinical information of GSE12021, GSE29746, GSE55235, GSE55457, GSE77298, and GSE89408 were adopted to perform differential expression gene analysis, enrichment, and immune component difference analyses of RA. Four machine learning algorithms, including LASSO, RF, XGBoost, and SVM, were used to identify RA-related biomarkers. Unsupervised cluster analysis was also used to decipher the heterogeneity of RA. A four-signature-based nomogram was constructed and verified to specifically diagnose RA and osteoarthritis (OA) from normal tissues. Consequently, RA-HFLS cell was utilized to investigate the biological role of CRTAM in RA. In addition, comparisons of diagnostic efficacy and biological roles among CRTAM and other classic biomarkers of RA were also performed. Results: Immune and stromal components were highly enriched in RA. Chemokine- and Th cell-related signatures were significantly activated in RA tissues. Four promising and novel biomarkers, including CRTAM, PTTG1IP, ITGB2, and MMP13, were identified and verified, which could be treated as novel treatment and diagnostic targets for RA. Nomograms based on the four signatures might aid in distinguishing and diagnosing RA, which reached a satisfactory performance in both training (AUC = 0.894) and testing (AUC = 0.843) cohorts. Two distinct subtypes of RA patients were identified, which further verified that these four signatures might be involved in the immune infiltration process. Furthermore, knockdown of CRTAM could significantly suppress the proliferation and invasion ability of RA cell line and thus could be treated as a novel therapeutic target. CRTAM owned a great diagnostic performance for RA than previous biomarkers including MMP3, S100A8, S100A9, IL6, COMP, LAG3, and ENTPD1. Mechanically, CRTAM could also be involved in the progression through immune dysfunction, fatty acid metabolism, and genomic instability across several cancer subtypes. Conclusion: CRTAM, PTTG1IP, ITGB2, and MMP13 were highly expressed in RA tissues and might function as pivotal diagnostic and treatment targets by deteriorating the immune dysfunction state. In addition, CRTAM might fuel cancer progression through immune signals, especially among RA patients.

A retrospective study on the mechanism underlying quick transfer from response to resistance in a repeated recurrent chordoma patient with molecular alterations treated with Palbociclib.

PURPOSE: There is no approved targeted therapy for chordoma at present. Although several preclinical studies have implied the potential applicability of CDK4/6 inhibitor for this rare tumor, no clinical evidence has been documented so far. The purpose of this study was to elucidate the therapeutic efficacy of CDK4/6 inhibitor for chordoma. METHODS: The next generation sequencing (as for whole-exome sequencing, WES assay) and immunohistochemical (IHC) staining of the chordoma tissue from a patient with an advanced lesion were performed before treatment. Then, the patient was treated with Palbociclib for 4 months until progression occurred in the 5th month. Surgical resection was implemented and the tumor tissue was obtained postoperatively for assessment of molecular alterations. RESULTS: Molecular features of the tumor before medical treatment suggested applicability of CDK4/6 inhibitor and the patient showed partial response (PR) according to Choi Criteria after 4 months treating with Palbociclib until progression occurred. Then, a drastic molecular alteration of the tumor as represented by emergence of dramatic E2F amplification, which is known to induce CDK4/6 independent cell-cycle entry and progression after treatment, was detected. The findings in this patient demonstrated tumor evolution under drug pressure. CONCLUSION: The findings of the present study suggest the feasibility of Palbociclib for the clinical treatment of chordoma, and imply the necessity of combination therapies rather single drug administration due to the quick resistance of the tumor to Palbociclib treatment.

Long-term postoperative outcomes of spinal cellular schwannoma: study of 93 consecutive cases.

BACKGROUND CONTEXT: Cellular schwannoma (CS) is a rare tumor that accounts for 2.8%-5.2% of all benign schwannomas. There is a dearth of up-to-date information on spinal CS in the literature. PURPOSE: The aims of this study were to identify the proportion of CS cases amongst spinal benign schwannoma, describe the clinical features of spinal CS, and identify prognostic factors for local recurrence by analyzing data from 93 consecutive CS cases. STUDY DESIGN: Retrospective review. PATIENT SAMPLE: We analyzed 93 PSGCT screened from 1,706 patients with spine CS who were treated at our institute between 2008 and 2021. OUTCOME MEASURES: Demographic, radiographic, operative and postoperative data were recorded and analyzed. METHODS: We compared the clinical features of spinal CS from the cervical, thoracic, lumbar and sacral segments. Prognostic factors for local recurrence-free survival (RFS) were identified by the Kaplan-Meier method. Factors with p≤.05 in univariate analysis were subjected to multivariate analysis by Cox regression analysis. RESULTS: The proportion of spinal CS in all benign schwannomas was 6.7%. The mean and median follow-up times for the 93 patients in this study were 92.2 and 91.0 months respectively (range 36-182 months). Local recurrence was detected in 11 cases, giving an overall recurrence rate of 11.7%, with one patient death. Statistical analysis revealed that tumor size ≥5 cm, intralesional resection, and Ki-67 ≥5% were independent negative prognostic factors for RFS in spinal CS. CONCLUSIONS: Whenever possible, en bloc resection is recommended for spinal CS. Long-term follow-up should be carried out for patients with tumor size ≥5 cm and postoperative pathological Ki-67 ≥5%.

A Novel and Reproducible Classification of Cervical Dumbbell Tumors to Inform Surgical Approach and Reconstruction Techniques.

STUDY DESIGN: A retrospective case series. OBJECTIVE: This study developed a novel classification system based on imaging and anatomy to select optimal surgical approaches and reconstruction strategies to achieve total resection of cervical dumbbell tumors and restore spinal stability. SUMMARY OF BACKGROUND DATA: Total resection is necessary to decrease the recurrence rate of cervical dumbbell tumors. Previous cervical dumbbell tumor classifications are insufficient for determining surgical strategies; therefore, a practical classification is needed. MATERIALS AND METHODS: This study included 295 consecutive patients with cervical dumbbell tumors who underwent total surgical resection. A novel classification of cervical dumbbell tumors was developed based on magnetic resonance imaging and computed tomography. Continuous variables were expressed as mean±SD and were compared using an unpaired two-tailed Student t test. The χ 2 test or the Fisher exact test was used for categorical variables. Kendall's W test assessed three independent raters' inter-rater and intrarater reliabilities on 140 cervical dumbbell tumors. RESULTS: The inter-rater and intrarater consistency coefficient was 0.969 (χ 2 =404.3, P <0.001) and 0.984 (χ 2 =273.7, P <0.001). All patients with type I and II tumors underwent single-posterior surgeries to achieve total resection. Of the patients in this study, 86.1%, 25.9%, 75.9%, and 76.9% underwent posterior surgeries for types IIIa, IIIb, IVa, and V tumors, respectively. All patients with type IVb tumors underwent a combined anterior and posterior approach. Posterior internal fixation was used for all patients in posterior surgery. Anterior reconstruction was applied for patients with type IVb tumors (20/20, 100%) and some with type V tumors (3/13, 23.1%). The mean follow-up duration was 93.6±2.6 months. A recurrence was observed in 19 (6.4%) patients. CONCLUSION: The authors describe a novel classification system that is of practical use for planning the complete resection of cervical dumbbell tumors.

Surgical Strategy for Recurrent Giant Cell Tumor in the Thoracolumbar Spine.

OBJECTIVE: Recurrent giant cell tumor (RGCT) of the spine represents a clinical challenge for surgeons, and the treatment strategy remains controversial. This study aims to describe the long-term follow-up outcomes and compare the efficacy of en bloc spondylectomy versus piecemeal spondylectomy in treating RGCT of the thoracolumbar spine. METHODS: A total of 32 patients with RGCT of the thoracolumbar spine treated from June 2012 to June 2019 were retrospectively reviewed. A total of 15 patients received total en bloc spondylectomy (TES) with wide or marginal margin while 17 patients received total piecemeal spondylectomy (TPS) with intralesional margin. Postoperative Eastern Cooperative Oncology Group Performance Score (ECOG-PS), Frankel classification and recurrence-free survival (RFS) were evaluated after surgery. Survival curves were estimated by the Kaplan-Meier method and differences were analyzed with the log-rank test. Multivariate analysis was performed with Cox regression to identify the independent prognostic factors affecting RFS. RESULTS: During a median follow-up of 41.9 ± 17.5 months, all patients with compromised neurologic functions exhibit significant improvement, with the mean ECOG-PS decreasing from 1.5 ± 1.3 to 0.13 ± 0.3 (p < 0.05). Among the 17 patients treated with TPS, eight patients developed local recurrence after a median time of 15.9 ± 6.4 months and four patients died from progressive disease. On the other hand, local recurrence were well managed with TES, since only one out of 15 patients experienced local relapse and all patients are alive with satisfied function at the latest follow-up. The median RFS for patients receiving TES and TPS are 75.0 months (95% CI: 67.5-82.5 m) and 38.3 months (95% CI: 27.3-49.3 m) respectively (p = 0.008). Multivariate analysis shows that the Ki67 index (p = 0.016), resection mode (p = 0.022), and denosumab (p = 0.039) are independent risk factors affecting RFS. CONCLUSIONS: TES with wide/marginal margin should be offered to patients with RGCT whenever feasible, given its long-term benefits in local control and symptom alleviation. Additionally, patients with lower Ki67 index and application of denosumab tend to have a better prognosis.

Regulating Chondro-Bone Metabolism for Treatment of Osteoarthritis via High-Permeability Micro/Nano Hydrogel Microspheres.

Destruction of cartilage due to the abnormal remodeling of subchondral bone (SB) leads to osteoarthritis (OA), and restoring chondro-bone metabolic homeostasis is the key to the treatment of OA. However, traditional intra-articular injections for the treatment of OA cannot directly break through the cartilage barrier to reach SB. In this study, the hydrothermal method is used to synthesize ultra-small size (≈5 nm) selenium-doped carbon quantum dots (Se-CQDs, SC), which conjugated with triphenylphosphine (TPP) to create TPP-Se-CQDs (SCT). Further, SCT is dynamically complexed with hyaluronic acid modified with aldehyde and methacrylic anhydride (AHAMA) to construct highly permeable micro/nano hydrogel microspheres (SCT@AHAMA) for restoring chondro-bone metabolic homeostasis. In vitro experiments confirmed that the selenium atoms scavenged reactive oxygen species (ROS) from the mitochondria of mononuclear macrophages, inhibited osteoclast differentiation and function, and suppressed early chondrocyte apoptosis to maintain a balance between cartilage matrix synthesis and catabolism. In vivo experiments further demonstrated that the delivery system inhibited osteoclastogenesis and H-vessel invasion, thereby regulating the initiation and process of abnormal bone remodeling and inhibiting cartilage degeneration in SB. In conclusion, the micro/nano hydrogel microspheres based on ultra-small quantum dots facilitate the efficient penetration of articular SB and regulate chondro-bone metabolism for OA treatment.

[Retracted] MicroRNA-493 inhibits the proliferation and invasion of osteosarcoma cells through directly targeting specificity protein 1.

[This retracts the article DOI: 10.3892/ol.2018.8268.].

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.

Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.