Scaling of Berry-curvature monopole dominated large linear positive magnetoresistance.

The linear positive magnetoresistance (LPMR) is a widely observed phenomenon in topological materials, which is promising for potential applications on topological spintronics. However, its mechanism remains ambiguous yet, and the effect is thus uncontrollable. Here, we report a quantitative scaling model that correlates the LPMR with the Berry curvature, based on a ferromagnetic Weyl semimetal CoS2 that bears the largest LPMR of over 500% at 2 K and 9 T, among known magnetic topological semimetals. In this system, masses of Weyl nodes existing near the Fermi level, revealed by theoretical calculations, serve as Berry-curvature monopoles and low-effective-mass carriers. Based on the Weyl picture, we propose a relation [Formula: see text], with B being the applied magnetic field and [Formula: see text] the average Berry curvature near the Fermi surface, and further introduce temperature factor to both MR/B slope (MR per unit field) and anomalous Hall conductivity, which establishes the connection between the model and experimental measurements. A clear picture of the linearly slowing down of carriers, i.e., the LPMR effect, is demonstrated under the cooperation of the k-space Berry curvature and real-space magnetic field. Our study not only provides experimental evidence of Berry curvature-induced LPMR but also promotes the common understanding and functional designing of the large Berry-curvature MR in topological Dirac/Weyl systems for magnetic sensing or information storage.

Inhibition of BUB1 suppresses tumorigenesis of osteosarcoma via blocking of PI3K/Akt and ERK pathways.

Osteosarcoma (OS) is a primary malignant bone tumour that mainly affects teenagers, with patients displaying poor prognosis. Budding uninhibited by benzimidazoles 1 (BUB1), a type of serine/threonine kinase that is linked to pro-tumorigenic phenomena, has not been well studied in OS. Hence, this study aimed to explore the role of BUB1 in OS. The expression of BUB1 in OS specimens and cell lines was assessed using immunohistochemistry and Western blot analysis. Univariate and multivariate analyses were applied to evaluate the impact of BUB1 on patient survival. Cell counting kit-8, wound-healing and Transwell assays, as well as flow cytometry, were used to investigate the influence of BUB1 inhibition on OS in vitro. Moreover, a tumour xenograft model was established to investigate the in vivo effect of BUB1 inhibition on OS tumour growth. Results showed that BUB1 was overexpressed in OS specimens and cell lines. Furthermore, BUB1 overexpression was closely associated with the poor clinical outcomes of patients with OS. Inhibition of BUB1 markedly suppressed cell proliferation and tumour growth, cell migration, invasion and induced cell apoptosis of OS by blocking the PI3K/Akt and ERK signalling pathways. Thus, our study suggested that overexpression of BUB1 protein contributed to poor survival of OS patients and that inhibition of BUB1 resulted in considerable anti-tumour activity associated with proliferation, migration, invasion and apoptosis of OS.

Ultrasensitive Detection of RNA with Single-Base Resolution by Coupling Electrochemical Sensing Strategy with Chimeric DNA Probe-Aided Ligase Chain Reaction.

Accurate and sensitive detection of single-base mutations in RNAs is of great value in basic studies of life science and medical diagnostics. However, the current available RNA detection methods are challenged by heterogeneous clinical samples in which trace RNA mutants usually existed in a large pool of normal wild sequences. Thus, there is still great need for developing the highly sensitive and highly specific methods in detecting single-base mutations of RNAs in heterogeneous clinical samples. In the present study, a new chimeric DNA probe-aided ligase chain reaction-based electrochemical method (cmDNA-eLCR) was developed for RNA mutation detection through the BSA-based carrier platform and the horseradish peroxidase-hydrogen peroxide-tetramethylbenzidine (HRP-H2O2-TMB) system. The denaturing polyacrylamide gel electrophoresis and a fluorophore-labeled probe was ingeniously designed to demonstrate the advantage of cmDNA in ligation to normal DNA templated by RNA with the catalysis of T4 RNA ligase 2 as well as its higher selectivity than DNA ligase system. Finally, the proposed cmDNA-eLCR, compared with the traditional eLCR, showed excellent performance in discriminating single base-mismatched sequences, where the signal response for mismatched targets at a high concentration could overlap completely with that for the blank control. Besides, this cmDNA-eLCR assay had a wide linear range crossing six orders of magnitude from 1.0 × 10-15 to1.0 × 10-10 M with a limit of detection as low as 0.6 fM. Furthermore, this assay was applied to detect RNA in real sample with a satisfactory result, thereby demonstrating its great potential in diagnosis of RNA-related diseases.

A pragmatic eLCR for an ultrasensitive detection of methicillin-resistant Staphylococcus aureus in joint synovial fluid: superior to qPCR.

For periprosthetic joint infection (PJI) patients, an early and rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) in joint synovial fluid is of great significance for receiving timely treatment and avoiding side effects. In clinical practice, the methods for detecting MRSA include the culture-based method and the PCR-based mecA gene detection method with fluorescent readout. However, the culture-based method requires up to 3-7 days for incubation and elaborative screening. The PCR-based molecular diagnosis, due to its high sensitivity, improves the detection time but sacrifices cost and gives false-positive results. Herein, a ligation chain reaction (LCR)-based electrochemical biosensor was developed to detect the mecA of MRSA with the advantages of rapidity, accuracy and low cost. In this system, an integrated dsDNA labeled with thiol and biotin at both terminals is generated only in the presence of the target DNA after LCR, followed by immobilization of the integrated dsDNAs on the bovine serum albumin (BSA)-coated gold electrode, and then the streptavidin horseradish peroxidase (SA-HRPs) is specifically bound to the biotin labels via biotin-streptavidin interaction, generating the catalytic amperometric readout. Impressively, the developed method achieved the detection of rare mecA in the joint synovial fluid of PJI patients (417-666 copies as quantified by qPCR). The proposed electrochemistry-based method is highly convenient for the point-of-care testing and was comparable with PCR in sensitivity, but superior in selectivity (single-base differentiation) and cost (nanomolar DNA probe consumption and simple device), demonstrating its huge potential in clinical applications for MRSA diagnosis.

Epidermal growth factor receptor promotes tumor progression and contributes to gemcitabine resistance in osteosarcoma.

Osteosarcoma (OS) is the most common type of primary malignant tumors that originate in the bone. Resistance to chemotherapy confers a poor prognosis on OS patients. Dysregulation of the epidermal growth factor receptor (EGFR) signaling has been reported in sarcomas. However, the functional contribution of EGFR hyperactivation to the tumor biology and chemoresistance remains largely unexplored in OS. In this study, we aimed to investigate the role of EGFR in OS progression and in the response of OS to gemcitabine treatment. The EGFR expression was found to be upregulated in fibroblastic OS cell lines. EGFR knockdown suppressed OS cell proliferation, migration, and invasion in vitro and tumor formation in vivo. Conversely, EGFR overexpression promoted the growth and motility of OS cells. In terms of mechanism, the levels of phospho-Akt and phospho-ERK were decreased upon EGFR knockdown but increased as a result of EGFR overexpression, implying a possible involvement of PI3K/Akt and ERK pathways in mediating the effects of EGFR on OS cells. Moreover, the level of phospho-EGFR was increased in OS cells when exposed to gemcitabine treatment. A more profound proliferative inhibition and a higher rate of apoptosis were obtained in OS cells via inducing cell cycle arrest at G1 phase upon gemcitabine treatment combined with EGFR knockdown, as compared to gemcitabine alone. On the contrary, EGFR overexpression counteracted the growth-inhibiting and pro-apoptotic effects of gemcitabine in OS cells. The present study suggests that EGFR promotes tumor progression and contributes to gemcitabine resistance in OS.

Stattic sensitizes osteosarcoma cells to epidermal growth factor receptor inhibitors via blocking the interleukin 6-induced STAT3 pathway.

Osteosarcoma (OS), the most common malignant bone tumor with high metastatic potential, frequently affects children and adolescents. Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors exhibit encouraging anti-tumor activity for patients with solid tumors, whereas their effects on OS remain controversial. In the present study, we aimed to elucidate the anti-tumor activity of gefitinib for OS, as well as to explore the underlying mechanisms. Gefitinib inhibits cell viability, tumor growth, cell migration, and invasion and promotes cell apoptosis and G1 cycle arrest in OS at a relatively high concentration via suppressing the PI3K/Akt and ERK pathways. However, gefitinib treatment results in the feedback activation of signal transducer and activator of transcription 3 (STAT3) induced by interleukin 6 (IL-6) secretion. Combined treatment with gefitinib and stattic, an inhibitor for STAT3 phosphorylation, engenders more evident inhibitory effects on cell proliferation, migration, and invasion and promotive effects on cell apoptosis and G1 phase arrest in OS, compared with the single exposure to gefitinib or stattic. Western blot analysis demonstrates that stattic treatment in gefitinib-treated OS abrogates the IL-6-induced STAT3 activation and subsequently further restrains the activities of EGFR, Akt, and ERK pathways in tumor cells. This study confirms that the EGFR inhibitor of gefitinib has moderate anti-tumor effects on OS through IL-6 secretion-mediated STAT3 activation. Additional administration of stattic in EGFR-targeted therapies may contribute to improve the efficacy for OS.

Clinicopathological and prognostic value of NADPH oxidase 2 (NOX2) in primary osteosarcoma.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor, particularly among children and adolescents, and the prognosis of osteosarcoma patients remains poor. The NADPH oxidase 2 (NOX2) has been found over-expressed in several human cancers, and closely associated with poor prognosis. Meanwhile the role of NOX2 in osteosarcoma patients has not been reported. This study aimed to investigate the clinicopathological and prognostic significance of NOX2 in osteosarcoma patients. METHODS: Immunohistochemistry (IHC), western blot (WB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression of NOX2 in 55 primary osteosarcoma specimens and in 20 non-neoplastic bone tissue specimens. The correlations between NOX2 expression and clinicopathological parameters were analysed by using the χ2 test or Fisher's exact test. Disease free survival and overall survival of osteosarcoma patients were assessed by using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: NOX2 was over-expressed significantly in osteosarcoma compared with that in non-neoplastic bone tissue, and correlated with progression free survival (P < 0.001) and overall survival (P < 0.001). The over-expression of NOX2 was associated with tumor size (P < 0.001), tumor location (P < 0.001). The Cox analysed shown that the over-expression of NOX2 was predicted to be worse PFS (hazard ratio (HR) = 4.10, P = 0.004) and OS (hazard ratio (HR) = 3.50, P = 0.010) time in osteosarcoma patients. CONCLUSIONS: The results of our study suggest that the over-expression of NOX2 is related to adverse clinical outcome, and can be viewed as an independent prognostic marker in osteosarcoma. Further research is required to verify the predictive value of NOX2 in osteosarcoma patients.

Prognostic role of the recepteur d'origine nantais (RON) expression in primary high-grade osteosarcoma.

BACKGROUND: Osteosarcoma is a common primary malignant bone tumor susceptible to distant metastasis. The clinical outcome for patients remains poor due to the resistance to chemotherapy and lacking effective therapeutic targets. Recepteur d'origine nantais (RON), a transmembrane protein of the c-MET proto-oncogene family, has been reported to contribute to the malignant progression and bone metastasis in several tumors. The present study aimed to explore the prognostic significance of RON in primary high-grade osteosarcoma. METHODS: Immunohistochemistry (IHC) and western blotting (WB) were used to investigate the protein expression of RON in 80 surgically resected specimens (50 high-grade osteosarcoma specimens and 30 non-neoplastic bone tissues) and 6 cell lines. The χ2 test or independent-sample Student's t-test was used to assess the significance of RON difference between osteosarcoma and non-neoplastic bone tissues. The χ2 test and Fisher's exact test were used to analyze the association of RON with the clinicopathological features of osteosarcoma patients. Kaplan-Meier method and Cox proportional hazards model were used to assess the significance of RON for the survival of osteosarcoma patients. RESULTS: The results of IHC and WB observed significant overexpression of RON in osteosarcoma specimens (P < 0.001) and osteosarcoma cell lines. Moreover, immunohistochemical high expression of RON was associated with a poor response to chemotherapy (P = 0.032) as well as worse progression-free (P = 0.003) and overall (P < 0.001) survival of osteosarcoma patients. Multivariate analysis revealed that high expression of RON was independently associated with reduced progression-free (P = 0.027, HR = 2.31) and overall survival (P = 0.004, HR = 5.06) time of osteosarcoma patients. CONCLUSIONS: The present study demonstrated that high expression of RON held independent value for unfavorable survival in primary high-grade osteosarcoma. Its potential role as a therapeutic target for osteosarcoma treatment deserves further research.

Coherent Resonant Tunneling through Double Metallic Quantum Well States.

Study of resonant tunneling through multimetallic quantum well (QW) structure is not only important for the fundamental understanding of quantum transport but also for the great potential to generate advanced functionalities of spintronic devices. However, it remains challenging to engineer such a structure due to the short electron phase coherence length in metallic QW system. Here, we demonstrate the successful fabrication of double-QW structure in a single fully epitaxial magnetic tunnel junction (MTJ) heterostructure, where two Fe QW layers are sandwiched between three MgAlO x tunnel barriers. We show clear evidence of the coherent resonant tunneling through the discrete QW states in the two QWs. The coherent resonant tunneling condition is fulfilled only when the middle barrier between the two QWs is thin enough and available QW states are present simultaneously in both QWs under a certain bias. Compared to the single QW structure, the resonant tunneling in double-QW MTJ produces strong conductivity oscillations with much narrower peak width (about half) owing to the enhanced energy filtering effect. This study presents a comprehensive understanding of the resonant tunneling mechanism in MTJ with multiple QWs, which is essential for future development of new spintronic devices operating in the quantum tunneling regime.

Full electrical manipulation of perpendicular exchange bias in ultrathin antiferromagnetic film with epitaxial strain.

Achieving effective manipulation of perpendicular exchange bias effect remains an intricate endeavor, yet it stands a significance for the evolution of ultra-high capacity and energy-efficient magnetic memory and logic devices. A persistent impediment to its practical applications is the reliance on external magnetic fields during the current-induced switching of exchange bias in perpendicularly magnetized structures. This study elucidates the achievement of a full electrical manipulation of the perpendicular exchange bias in the multilayers with an ultrathin antiferromagnetic layer. Owing to the anisotropic epitaxial strain in the 2-nm-thick IrMn3 layer, the considerable exchange bias effect is clearly achieved at room temperature. Concomitantly, a specific global uncompensated magnetization manifests in the IrMn3 layer, facilitating the switching of the irreversible portion of the uncompensated magnetization. Consequently, the perpendicular exchange bias can be manipulated by only applying pulsed current, notably independent of the presence of any external magnetic fields.

Tailoring of the Interfacial Dzyaloshinskii-Moriya Interaction in Perpendicularly Magnetized Epitaxial Multilayers by Crystal Engineering.

The interplay between the interfacial crystalline structure and Dzyaloshinskii-Moriya interaction (DMI) was investigated by Fe insertion in epitaxial Pt/Co/Ir perpendicular magnetized multilayers. The experimental results with the support of first-principles calculation indicate that the Fe/Ir interface exhibits a positive interfacial DMI (iDMI) originating from the fcc crystalline structure inserted by 2 monolayers (ML) Fe, while a negative one from the structure with a layer shifting of 1-ML Fe insertion. The total iDMI of the multilayers increases (decreases) due to the additive enhancement (competitive counteraction) between the iDMI of Fe/Ir and Pt/Co interfaces. Comparing the iDMI of single-crystalline and textured multilayers, the iDMI of multilayers is found to be particularly sensitive to the crystallinity nearby the heterointerfaces. This work is of vital importance to reveal a deeper insight into the physical mechanism of the iDMI and provides a viable strategy for tailoring the iDMI of the multilayers by crystal engineering.

Magnetic-field modulation of topological electronic state and emergent magneto-transport in a magnetic Weyl semimetal.

The modulation of topological electronic state by an external magnetic field is highly desired for condensed-matter physics. Schemes to achieve this have been proposed theoretically, but few can be realized experimentally. Here, combining transverse transport, theoretical calculations, and scanning tunneling microscopy/spectroscopy (STM/S) investigations, we provide an observation that the topological electronic state, accompanied by an emergent magneto-transport phenomenon, was modulated by applying magnetic field through induced non-collinear magnetism in the magnetic Weyl semimetal EuB6. A giant unconventional anomalous Hall effect (UAHE) is found during the magnetization re-orientation from easy axes to hard ones in magnetic field, with a UAHE peak around the low field of 5 kOe. Under the reasonable spin-canting effect, the folding of the topological anti-crossing bands occurs, generating a strong Berry curvature that accounts for the observed UAHE. Field-dependent STM/S reveals a highly synchronous evolution of electronic density of states, with a dI/dV peak around the same field of 5 kOe, which provides evidence to the folded bands and excited UAHE by external magnetic fields. This finding elucidates the connection between the real-space non-collinear magnetism and the k-space topological electronic state and establishes a novel manner to engineer the magneto-transport behaviors of correlated electrons for future topological spintronics.

Room temperature field-free switching of perpendicular magnetization through spin-orbit torque originating from low-symmetry type II Weyl semimetal.

Spin-orbit torque (SOT) is a promising strategy to deterministically switch the perpendicular magnetization, but usually requires an in-plane magnetic field for breaking the mirror symmetry, which is not suitable for most advanced industrial applications. Van der Waals (vdW) materials with low crystalline symmetry and topological band structures, e.g., Weyl semimetals (WSMs), potentially serve as an outstanding system that may simultaneously realize field-free switching and high energy efficiency. Yet, the demonstration of these superiorities at room temperature has not been realized. Here, we achieve a field-free switching of perpendicular magnetization by using a layered type II WSM, TaIrTe4, in a TaIrTe4/Ti/CoFeB system at room temperature with the critical switching current density ~2.4 × 106 A cm-2. The field-free switching is ascribed to the out-of-plane SOT allowed by the low crystal symmetry. Our work suggests that using low-symmetry materials to generate SOT is a promising route for the manipulation of perpendicular magnetization at room temperature.

Electrical detection of spin pumping in van der Waals ferromagnetic Cr2Ge2Te6 with low magnetic damping.

The discovery of magnetic order in atomically-thin van der Waals materials has strengthened the alliance between spintronics and two-dimensional materials. An important use of magnetic two-dimensional materials in spintronic devices, which has not yet been demonstrated, would be for coherent spin injection via the spin-pumping effect. Here, we report spin pumping from Cr2Ge2Te6 into Pt or W and detection of the spin current by inverse spin Hall effect. The magnetization dynamics of the hybrid Cr2Ge2Te6/Pt system are measured, and a magnetic damping constant of ~ 4-10 × 10-4 is obtained for thick Cr2Ge2Te6 flakes, a record low for ferromagnetic van der Waals materials. Moreover, a high interface spin transmission efficiency (a spin mixing conductance of 2.4 × 1019/m2) is directly extracted, which is instrumental in delivering spin-related quantities such as spin angular momentum and spin-orbit torque across an interface of the van der Waals system. The low magnetic damping that promotes efficient spin current generation together with high interfacial spin transmission efficiency suggests promising applications for integrating Cr2Ge2Te6 into low-temperature two-dimensional spintronic devices as the source of coherent spin or magnon current.

Mesenchymal Stem Cell Derived Exosomes as Nanodrug Carrier of Doxorubicin for Targeted Osteosarcoma Therapy via SDF1-CXCR4 Axis.

Purpose: The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and exosome (Exo-Dox) derived from mesenchymal stem cells in vitro and in vivo. Methods: The exosomes were isolated with Exosome Isolation Kit, and the Exo-Dox was prepared by mixing exosome with Dox-HCl, desalinizing with triethylamine and then dialyzing against PBS overnight. The exosome and Exo-Dox were examined by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). The antitumor activity, targeting capability, and mechanism of the developed Exo-Dox were evaluated by cell viability assay, histological and immunofluorescence analysis and in vivo imaging system. Results: NTA results showed the size of the exosomes had increased from 141.6 nm to 178.1 nm after loading with doxorubicin. Compared with free Dox, the Exo-Dox exhibited higher cytotoxicity against osteosarcoma MG63 cells, HOS cells, and 143B cells than free Dox, the half-maximal inhibitory concentrations (IC50) of Dox, Exo-Dox were calculated to be 0.178 and 0.078 µg mL-1 in MG63 cells, 0.294 and 0.109µg mL-1 in HOS cells, 0.315 and 0.123 µg mL-1 in 143B cells, respectively. The in vivo imaging showed that MSC derived Exo could serve as a highly efficient delivery vehicle for targeted drug delivery. The immunohistochemistry and histology analysis indicated that compared with the free Dox group, the Ki67-positive cells and cardiotoxicity in Exo-Dox group were significantly decreased. Conclusion: Our results suggested that MSC-derived Exo could be excellent nanocarriers used to deliver chemotherapeutic drug Dox specifically and efficiently in osteosarcoma, resulting in enhanced toxicity against osteosarcoma and less toxicity in heart tissue. We further demonstrated the targeting capability of Exo was due to the chemotaxis of MSC-derived exosomes to osteosarcoma cells via SDF1-CXCR4 axis.

Promote or Inhibit: Economic Goal Pressure and Residents' Health.

This paper aimed to identify the relationship between the pressure to reach economic growth targets and residents' health by applying a panel fixed effects model, a Sobel-Goodman mediation effects test and a regulatory effects model to the inland provinces of China. The empirical results verify that the pressure to reach economic growth targets in these regions reduces the level of residents' health. Moreover, the effect in developing regions is significantly stronger than that in developed regions, and the effect in the northern region is significantly stronger than that in the southern region. The mediation effects test found that the pressure to reach economic growth targets has led to an upsurge in PM2.5 concentration and an increase in the output of industrial solid waste, thereby threatening residents' health. The regulatory effects model highlights that enhancing public awareness could weaken the negative impact of the pressure to reach economic growth targets on residents' health, while the expansion of industrial production will aggravate the negative impact. In the process of economic growth, the government should set reasonable economic growth targets, pay attention to the construction of the environmental protection legal system, implement energy- conservation and emission reduction measures and increase public awareness of environmental protection to ensure residents' health.

The Impact of Digital Economy on Residents' Health: Based on the Perspective of Population Ageing.

This paper uses panel data from inland provinces of China to perform a fixed effect regression and finds that the development of the digital economy has a significant promotional effect on the health of residents. Then, the population ageing rate is further used as a threshold variable for a threshold regression, and the relationship between the development of the digital economy and the health of residents from the perspective of ageing is discussed. The empirical results show that the ageing of the population will reduce the role of the digital economy in promoting residents' health. There is a non-linear single threshold effect between the development of the digital economy and residents' health indicators. In areas of China with a better developed digital economy, when the ageing rate exceeds the threshold, the positive impact of the development of the digital economy on population health has increased compared with the population ageing below the threshold. These asymmetric developments are closely related to economic development, historical and cultural factors, and policies formulated by the government. Therefore, as the digital economy continues to advance, the government should also provide health services fairly and efficiently, and formulate effective Internet assistance policies for the elderly so that the development of the digital economy can more comprehensively promote the health of residents of all ages.

Corrigendum: NLRP3 Overexpression Associated With Poor Prognosis and Presented as an Effective Therapeutic Target in Osteosarcoma.

[This corrects the article DOI: 10.3389/fphar.2021.724923.].

The Clinical Significance of the Expression of FEN1 in Primary Osteosarcoma.

PURPOSE: The aim of this research was to investigate the clinical significance of the expression of flap structure-specific endonuclease 1 (FEN1) in primary osteosarcoma. METHODS: The expression of FEN1 was detected by immunohistochemistry analysis. The association of the expression of FEN1 in osteosarcoma with clinicopathological parameters was analyzed by using χ 2 test or Fisher's exact test. Survival analyses were performed by Kaplan-Meier method and Cox proportional hazards regression model. RESULTS: Of the 40 osteosarcoma patients, 19 (47.5%) patients presented with FEN1 high expression, while in the non-neoplastic bone specimens, the FEN1 high expression was observed in 10% (3/30), the positive expression rate in osteosarcoma patients was significantly higher than that of non-neoplastic bone specimens (P< 0.01). Univariate analysis indicated that the progression-free survival (PFS) and overall survival (OS) were correlated with the expression level of FEN1 (PFS, P < 0.001; OS, P = 0.002), Enneking staging (PFS, P = 0.026; OS, P = 0.044) and chemotherapy response (PFS, P = 0.019; OS, P = 0.031). Multivariate analysis demonstrated that FEN1 expression was an independent prognostic factor for the PFS (HR = 4.73, P = 0.002) and OS (HR = 4.01, P = 0.038) of osteosarcoma patients. CONCLUSION: This study showed that FEN1 was overexpressed in osteosarcoma patients and positively associated with poor prognosis of osteosarcoma patients. Further studies should focus on the relative mechanisms and the targeted FEN1 therapies for osteosarcoma.

NLRP3 Overexpression Associated With Poor Prognosis and Presented as an Effective Therapeutic Target in Osteosarcoma.

Despite the development of diagnostic and treatment strategies, the survival outcome of patients with osteosarcoma remains poor. Nod-like receptor protein 3 (NLRP3) plays a crucial role in the inflammasome pathway, which is related to the progression of various tumors. However, the effect of NLRP3 on osteosarcoma has not yet been well explored. Our study aimed to investigate the role of NLRP3 in the malignant biological behavior of osteosarcoma as well as its therapeutic value. Immunohistochemistry was applied to investigate the NLRP3 expression in osteosarcoma and osteochondroma specimens. Cell Counting Kit-8, colony formation, wound healing, transwell, and flow cytometry assays were used to explore the contribution of NLRP3 to the proliferation, migration, invasion, apoptosis and cell cycle distribution of osteosarcoma cells in vitro. Western blot was performed to evaluate the expression of NLRP3 and the related proteins in osteosarcoma cell lines after the blockade of NLRP3 using CY-09 and lentivirus intervention. Furthermore, tumor formation assay was used to analyze the effect of NLRP3 on the growth of osteosarcoma in vivo. The results showed that the NLRP3 protein was overexpressed in osteosarcoma, which was independently correlated with the poor prognosis of patients. Moreover, NLRP3 suppression by the inhibitor of CY-09 or lentivirus-induced gene knockdown inhibited the cell proliferation, migration, invasion and promoted the cell apoptosis and G1 cell cycle arrest in osteosarcoma via targeting the inflammasome pathway. Our in vivo results confirmed that the inhibition of NLRP3 suppressed the tumor formation of osteosarcoma. In conclusion, NLRP3 may be regarded as an independent prognostic biomarker and a potential therapeutic target for osteosarcoma.