Low NT5DC2 expression predicts favorable prognosis and suppresses soft tissue sarcoma progression via ECM-receptor interaction pathway.

BACKGROUND: Soft tissue sarcoma, a malignant tumor arising from mesenchymal tissues with poor prognosis. 5'-Nucleotidase Domain Containing 2 (NT5DC2) is a novel oncogene, and the precise involvement of NT5DC2 in soft tissue sarcoma were still undefined. Hence, our study aims to investigate NT5DC2 functions in soft tissue sarcoma progression. METHODS: The tumor immune single-cell hub 2 (TISCH2) website, The Cancer Genome Atlas (TCGA) pan-cancer or sarcoma and Gene Expression Omnibus (GEO, GSE21122) databases were applied to visualize the NT5DC2 status in the sarcoma databases. The NT5DC2 protein expression in sarcoma tissues in our hospital was detected by using immunohistochemistry (IHC) and analyzed the associations between NT5DC2 expression and clinicopathological parameters. Real-time quantitative polymerase chain reaction (RT-qPCR), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing, transwell, flow cytometry and xenograft model were used to elucidate the effects of NT5DC2 downregulated by lentivirus in sarcoma cell. RESULTS: The TISCH2 website detection found that NT5DC2 expression is enriched in malignant cells in sarcoma single-cell database. Furthermore, the TCGA-sarcoma database indicated that NT5DC2 expression correlates with metastasis, positive margin status, prognosis, and diagnostic value. Additionally, IHC staining showed that 40 % of soft tissue sarcoma patients present high expression of NT5DC2, and NT5DC2 upregulation is closely associated with poor prognosis. Functional verification analysis further revealed that downregulating NT5DC2 expression can suppress sarcoma progression through the ECM-receptor interaction pathway. CONCLUSION: Low expression of NT5DC2 predicts a favorable prognosis in soft tissue sarcoma, and downregulated NT5DC2 expression can suppress sarcoma cell progression through the ECM-receptor interaction pathway.

Identifying squalene epoxidase as a metabolic vulnerability in high-risk osteosarcoma using an artificial intelligence-derived prognostic index.

BACKGROUND: Osteosarcoma (OSA) presents a clinical challenge and has a low 5-year survival rate. Currently, the lack of advanced stratification models makes personalized therapy difficult. This study aims to identify novel biomarkers to stratify high-risk OSA patients and guide treatment. METHODS: We combined 10 machine-learning algorithms into 101 combinations, from which the optimal model was established for predicting overall survival based on transcriptomic profiles for 254 samples. Alterations in transcriptomic, genomic and epigenomic landscapes were assessed to elucidate mechanisms driving poor prognosis. Single-cell RNA sequencing (scRNA-seq) unveiled genes overexpressed in OSA cells as potential therapeutic targets, one of which was validated via tissue staining, knockdown and pharmacological inhibition. We characterized changes in multiple phenotypes, including proliferation, colony formation, migration, invasion, apoptosis, chemosensitivity and in vivo tumourigenicity. RNA-seq and Western blotting elucidated the impact of squalene epoxidase (SQLE) suppression on signalling pathways. RESULTS: The artificial intelligence-derived prognostic index (AIDPI), generated by our model, was an independent prognostic biomarker, outperforming clinicopathological factors and previously published signatures. Incorporating the AIDPI with clinical factors into a nomogram improved predictive accuracy. For user convenience, both the model and nomogram are accessible online. Patients in the high-AIDPI group exhibited chemoresistance, coupled with overexpression of MYC and SQLE, increased mTORC1 signalling, disrupted PI3K-Akt signalling, and diminished immune infiltration. ScRNA-seq revealed high expression of MYC and SQLE in OSA cells. Elevated SQLE expression correlated with chemoresistance and worse outcomes in OSA patients. Therapeutically, silencing SQLE suppressed OSA malignancy and enhanced chemosensitivity, mediated by cholesterol depletion and suppression of the FAK/PI3K/Akt/mTOR pathway. Furthermore, the SQLE-specific inhibitor FR194738 demonstrated anti-OSA effects in vivo and exhibited synergistic effects with chemotherapeutic agents. CONCLUSIONS: AIDPI is a robust biomarker for identifying the high-risk subset of OSA patients. The SQLE protein emerges as a metabolic vulnerability in these patients, providing a target with translational potential.

Design of 3D-printed prostheses for reconstruction of periacetabular bone tumors using topology optimization.

Background: Prostheses for the reconstruction of periacetabular bone tumors are prone to instigate stress shielding. The purpose of this study is to design 3D-printed prostheses with topology optimization (TO) for the reconstruction of periacetabular bone tumors and to add porous structures to reduce stress shielding and facilitate integration between prostheses and host bone. Methods: Utilizing patient CT data, we constructed a finite element analysis (FEA) model. Subsequent phases encompassed carrying out TO on the designated area, utilizing the solid isotropic material penalization model (SIMP), and this optimized removal area was replaced with a porous structure. Further analyses included preoperative FEA simulations to comparatively evaluate parameters, including maximum stress, stress distribution, strain energy density (SED), and the relative micromotion of prostheses before and after TO. Furthermore, FEA based on patients' postoperative CT data was conducted again to assess the potential risk of stress shielding subsequent to implantation. Ultimately, preliminary follow-up findings from two patients were documented. Results: In both prostheses, the SED before and after TO increased by 143.61% (from 0.10322 to 0.25145 mJ/mm3) and 35.050% (from 0.30964 to 0.41817 mJ/mm3) respectively, showing significant differences (p < 0.001). The peak stress in the Type II prosthesis decreased by 10.494% (from 77.227 to 69.123 MPa), while there was no significant change in peak stress for the Type I prosthesis. There were no significant changes in stress distribution or the proportion of regions with micromotion less than 28 µm before and after TO for either prosthesis. Postoperative FEA verified results showed that the stress in the pelvis and prostheses remained at relatively low levels. The results of follow-up showed that the patients had successful osseointegration and their MSTS scores at the 12th month after surgery were both 100%. Conclusion: These two types of 3D-printed porous prostheses using TO for periacetabular bone tumor reconstruction offer advantages over traditional prostheses by reducing stress shielding and promoting osseointegration, while maintaining the original stiffness of the prosthesis. Furthermore, in vivo experiments show that these prostheses meet the requirements for daily activities of patients. This study provides a valuable reference for the design of future periacetabular bone tumor reconstruction prostheses.

(E)-SIS3 suppressed osteosarcoma progression via promoting cell apoptosis, arresting cell cycle, and regulating the tumor immune microenvironment.

Osteosarcoma is a prevalent malignant bone tumor with a poor prognosis. Mothers against decapentaplegic homolog 3 (Smad3) present as a therapeutic target in antitumor treatment, whereas its functions in the osteosarcoma have not been well explored. In the current study, we aimed to investigate the effects of Smad3 in the progression of osteosarcoma. The tumor immune single-cell hub 2 website was used for graph-based visualization of Smad3 status in osteosarcoma single-cell database. Western Blot was applied to detect the expression of Smad3 protein in cell lines. Colony formation and cell counting kit-8 assays were used to evaluate cell proliferation. Transwell and wound healing assays were used to detect the migration and invasion abilities of cells. Cell apoptosis rates and cell cycle changes were explored by using flow cytometry analysis. The xenograft tumor growth model was applied to explore the effect in tumor growth after Smad3 blockage in vivo. Moreover, to confirm the potential mechanism of Smad3's effects on osteosarcoma, bioinformatics analysis was performed in TARGET-Osteosarcoma and GSE19276 databases. Our study found that the Smad3 protein is overexpressed in 143B and U2OS cells, suppressing the expression of Smad3 protein in osteosarcoma cells by Smad3 target inhibitor (E)-SIS3 or lentivirus can inhibit the proliferation, migration, invasion, promote cell apoptosis, arrest cell G1 cycle in osteosarcoma cells in vitro, and suppress tumor growth in vivo. Furthermore, the bioinformatics analysis demonstrated that high expression of Smad3 is closely associated with low immune status in TARGET-Osteosarcoma and GSE19276 databases. Our study suggested that Smad3 could contribute positively to osteosarcoma progression via the regulation of tumor immune microenvironment, and Smad3 may represent as an valuable potential therapeutic target in osteosarcoma therapy.

Surgical robot-assisted tripod percutaneous reconstruction technique combined with bone cement filling technique for the treatment of acetabular metastasis.

Background: Acetabular metastasis is a type of metastatic bone cancer, and it mainly metastasizes from cancers such as lung cancer, breast cancer, and renal carcinoma. Acetabular metastasis often causes severe pain, pathological fractures, and hypercalcemia which may seriously affect the quality of life of acetabular metastasis patients. Due to the characteristics of acetabular metastasis, there is no most suitable treatment to address it. Therefore, our study aimed to investigate a novel treatment technique to relieve these symptoms. Methods: Our study explored a novel technique to reconstruct the stability of the acetabular structure. A surgical robot was used for accurate positioning and larger-bore cannulated screws were accurately inserted under the robot's guidance. Then, the lesion was curetted and bone cement was injected through a screw channel to further strengthen the structure and kill tumor cells. Results: A total of five acetabular metastasis patients received this novel treatment technique. The data relating to surgery were collected and analyzed. The results found that this novel technique can significantly reduce operation time, intraoperative bleeding, visual analogue score scores, Eastern Cooperative Oncology Group scores, and postoperative complications (e.g., infection, implant loosening, hip dislocation) after treatment. Follow-up time ranged from 3 months to 6 months, and the most recent follow-up results showed that all patients survived and no acetabular metastasis progressed in any of the patients after surgery. Conclusion: Surgical robot-assisted tripod percutaneous reconstruction combined with the bone cement filling technique may be a novel and suitable treatment in acetabular metastasis patients. Our study may provide new insights into the treatment of acetabular metastasis.

Combination of hsa_circ_0004674 and lncRNA OIP5­AS1 as a novel clinical biomarker used to predict prognosis in patients with osteosarcoma.

Osteosarcoma is a malignant tumor that predominantly occurs in children or adolescents under the age of 20 years old. Metastasis and chemotherapy resistance are two problems in the treatment of osteosarcoma, and the lack of definite biomarkers impairs the course of treatment. In recent years, non-coding RNA, as a biomarker of osteosarcoma, has become an area of research focus. The role of long non-coding RNAs (lncRNAs), such as lncRNA OIP5-AS1, and circular RNAs, such as hsa_circ_0004674, in osteosarcoma have previously been revealed, and the present study investigated their clinical significance. A total of 20 samples were collected from patients with osteosarcoma. The expression levels of lncRNA OIP5-AS1 and hsa_circ_0004674 were analyzed in tumor tissues and patient serum, and their associations with chemotherapy sensitivity, lung metastasis and prognosis were assessed. The results revealed that these two non-coding RNAs were significantly upregulated in the osteosarcoma tissues of patients compared with those in the adjacent tumor tissues. In addition, the expression levels of the two non-coding RNAs were increased in the serum of patients with osteosarcoma compared with those in patients with bone fractures (P<0.01). In patients with lung metastasis or chemotherapy resistance (tumor necrosis rate <90%), the expression levels of the two non-coding RNAs were similarly increased. By plotting the receiver operating characteristic curve, it was revealed that the combination of hsa_circ_0004674 and lncRNA OIP5-AS1 was better than ALP or either non-coding RNA alone in predicting chemotherapy sensitivity and metastasis. Kaplan-Meier survival analysis showed that, in patients with osteosarcoma, higher expression of both non-coding RNAs was associated with worse survival time (log-rank test P=0.006). In conclusion, the combination of hsa_circ_0004674 and lncRNA OIP5-AS1 may be used as a better biomarker than traditional biomarkers, such as ALP, in a clinical setting.

Refracture after plate removal of midshaft clavicle fractures after bone union-incidence, risk factors, management and outcomes.

INTRODUCTION: There is a great debate on the routine use of open reduction and internal fixation (ORIF) for midshaft clavicle fractures, and one concern is the adverse events after ORIF, such as implant removal after bone union. In this retrospective study, we assessed the incidence, risk factors, management and outcomes of refracture after plate removal of midshaft clavicle fractures after bone union. MATERIALS AND METHODS: Three hundred fifty-two patients diagnosed with acute midshaft clavicle fractures who had complete medical records from primary fractures to refracture were recruited. Details of imaging materials and clinical characteristics were carefully reviewed and analysed. RESULTS: The incidence rate of refracture was 6.5% (23/352), and the average interval from implant removal to refracture was 25.6 days. Multivariate analysis showed that the risk factors were Robinson type-2B2 and fair/poor reduction. Females were 2.4 times more likely to have refracture, although it was not significant in multivariate analysis (p = 0.134). Postmenopausal females with a short interval (≤ 12 months) from primary surgery to implant removal had a significant risk for refracture. Tobacco use and alcohol use during bone healing were potential risk factors for male patients, although they were not significant in multivariate analysis. Ten patients received reoperation with or without bone graft, and they had a higher rate of bone union than 13 patients who refused reoperation. CONCLUSION: The incidence of refracture following implant removal after bone union is underestimated, and severe comminute fractures and unsatisfactory reduction during primary surgery are risk factors. Implant removal for postmenopausal female patients is not recommended due to a high rate of refracture.

LncRNA ODRUL regulates progression of osteosarcoma by regulating IL-6 via sponging miR-6874-3p.

Accumulating evidence has shown that many long non-coding RNAs (lncRNA) participate in the tumorigenesis, including osteosarcoma (OS). Of them, lncRNA ODRUL was previously reported to act as a possible oncogene in OS doxorubicin resistance. However, the underlying molecular mechanism of ODRUL involved in the progression of OS still remains to be thoroughly investigated. In the current study, we reported another mechanism by which ODRUL regulates OS progression. QRT-PCR and WB were conducted to detect ODRUL, miR-6874-3p and IL-6 expression in OS tissues and cells. The Kaplan-Meier was used to assess the relevance between the expression level of miR-6874-3p and the overall survival of OS patients. Wound healing assays and Transwell assays were used to evaluate the invasion and migration of OS cells. Furthermore, the binding sites of ODRUL and IL-6 to miR-6874-3p were predicted by bioinformatics and verified by dual-luciferase reporter gene assays. ODRUL and IL-6 were highly expressed in OS cells and tissues, while miR-6874-3p was expressed at low levels. The overall survival of high miR-6874-3p expression of OS patients was longer than that of low miR-6874-3p expression of OS patients. MiR-6874-3p overexpression markedly inhibited the progression of OS cells. Both ODRUL and IL-6 could bind to miR-6874-3p at the predicted binding sites which were authenticated by dual-luciferase reporter gene assay. MiR-6874-3p could inhibit OS cell proliferation and metastasis and ODRUL could reverse the suppression induced by miR-6874-3p in vivo. In conclusion, ODRUL could effectively sponge miR-6874-3p to upregulate the expression of IL-6 in OS progression.

Biomineralization-inspired synthesis of amorphous manganese phosphates for GLUT5-targeted drug-free catalytic therapy of osteosarcoma.

Osteosarcoma, occurring most frequently in children, teens, and young adults, is a lethal bone cancer with a high incidence of distant metastases and drug resistance. Developing a therapeutic platform that integrates targeting, curing and imaging is highly desirable for enhanced osteosarcoma therapy, yet quite challenging. In this work, we demonstrate a novel biomineralization-inspired strategy for the synthesis of a fructose incorporated manganese phosphate (Fru-MnP) nanoplatform for tumour targeting, drug-free therapy, and MRI imaging. Benefitting from the glucose transporter 5 (GLUT5)-mediated endocytosis, our Fru-MnP nanoplatform produces a high level of reactive oxygen species (ROS) via the Mn2+-driven Fenton reaction within osteosarcoma cells, leading to efficient cancer cell killing due to caspase-mediated apoptosis. By virtue of the T1 signal enhancement of Mn2+, our Fru-MnP nanoplatform also acts as an effective tumour-specific MRI contrast agent, realizing the MRI-monitored chemodynamic therapy. The proposed synergistic therapeutic platform opens new possibilities for high efficacy therapy for osteosarcoma.

Doxorubicin-induced novel circRNA_0004674 facilitates osteosarcoma progression and chemoresistance by upregulating MCL1 through miR-142-5p.

Accumulating evidence has shown that circular RNA (circRNA) dysregulation is involved in various types of cancer, including osteosarcoma (OS). Nevertheless, the role and mechanism of circRNAs in OS progression and chemoresistance remain elusive. We found that a novel doxorubicin-induced circular RNA, hsa_circ_0004674, screened by whole total transcriptome RNA sequencing in our previous study, was upregulated in OS chemoresistant cell lines and tissues and also connected with patients' poor prognosis. Circ_0004674 knockdown remarkably suppressed OS cell chemoresistance, proliferation, migration, invasion, OS tumor growth, and enhanced cell cycle arrest and apoptosis in vitro and in vivo through control the expression of the antiapoptotic protein MCL1, a member of the Bcl-2 gene family. Further online bioinformatics analysis revealed that miR-142-5p had potential binding sites that can bind circ_0004674 and the 3'UTR of MCL1 mRNA. Moreover, the expression and function of miR-142-5p were conversely correlated with circ_0004674 in vitro. RIP, pull-down, luciferase assay, and RNA FISH demonstrated that circ_0004674 could compete with MCL1 for miR-142-5p binding to counteract miR-142-5p-mediated repression of MCL1 at the post-transcriptional level. To sum up, our study sheds light on the critical role of the oncogenic circ_0004674/miR-142-5p/MCL1 axis in OS progression and chemoresistance, providing a novel potential target for OS therapy.

The Thermo-Mechanical Coupling Effect in Selective Laser Melting of Aluminum Alloy Powder.

In the selective laser melting process, metal powder melted by the laser heat source generates large instantaneous energy, resulting in transient high temperature and complex stress distribution. Different temperature gradients and anisotropy finally determine the microstructure after melting and affect the build quality and mechanical properties as a result. It is important to monitor and investigate the temperature and stress distribution evolution. Due to the difficulties in online monitoring, finite element methods (FEM) are used to simulate and predict the building process in real time. In this paper, a thermo-mechanical coupled FEM model is developed to predict the thermal behaviors of the melt pool by using Gaussian moving heat source. The model could simulate the shapes of the melt pool, distributions of temperature and stress under different process parameters through FEM. The influences of scanning speed, laser power, and spot diameter on the distribution of the melt pool temperature and stress are investigated in the SLM process of Al6063, which is widely applied in aerospace, transportation, construction and other fields due to its good corrosion resistance, sufficient strength and excellent process performance. Based on transient analysis, the relationships are identified among these process parameters and the melt pool morphology, distribution of temperature and thermal stress. It is shown that the maximum temperature at the center point of the scanning tracks will gradually increase with the increment of laser power under the effect of thermal accumulation and heat conduction, as the preceded scanning will preheat the subsequent scanning tracks. It is recommended that the parameters with optimized laser power (P = 175-200 W), scanning speed (v = 200-300 mm/s) and spot diameter (D = 0.1-0.15 mm) of aluminum alloy powder can produce a high building quality of the SLM parts under the pre-set conditions.

Retrospective Clinical Evaluation of Negative-Pressure Wound Therapy for Infection Prevention Following Malignant Pelvic Bone Tumor Resection Reconstruction.

OBJECTIVE: To evaluate the clinical outcomes of negative-pressure wound therapy (NPWT) for infection prevention following pelvic reconstruction after malignant bone tumor resection. METHODS: The study involved 82 patients who underwent pelvic reconstruction following en-bloc resection of malignant bone tumors between January 2003 and January 2016. Forty patients were treated with NPWT via implantation of vacuum-sealing drainage (VSD) materials into the pelvic cavity to prevent infection and wound problems (VSD group), and the remaining 42 patients underwent conventional treatment (control group). Study authors compared the inpatient length of stay, antibiotic use, drainage volume, time to wound closure, and infection rates between groups. Investigators also conducted cell cultures of the wound cavity washing fluid and hematoxylin-eosin staining for VSD materials to find recurrent tumor cells. RESULTS: In the VSD group, one patient (2.5%) had a superficial wound problem. In the control group, 18 patients (42.9%) had deep infection or wound problems. The VSD group had a significantly decreased infection rate, duration of antibiotic administration and inpatient stay, as well as increased wound healing compared with the control group (P < .05). Further, no tumor cells were observed in the VSD material or the wound cavity washing fluid. CONCLUSIONS: The application of NPWT with VSD material may be an effective and reliable method for preventing infection in patients who undergo pelvic reconstruction following malignant tumor resection.

Selenium-doped calcium phosphate biomineral reverses multidrug resistance to enhance bone tumor chemotherapy.

The construction of a functional drug delivery system to reverse the multidrug resistance (MDR) of bone tumors in cases of failed chemotherapy remains a challenge. Herein, we demonstrate a selenium-doped calcium phosphate (Se-CaP) biomineral with high biocompatibility, biodegradability and pH-sensitive drug release properties. Se-CaP may not only serve as an effective drug-carrier to enhance the uptake of doxorubicin (DOX), but may also synchronously induce caspases-mediated apoptosis of osteosarcoma by generating intracellular reactive oxygen species (ROS). Furthermore, in vitro and in vivo studies obviously demonstrate that Se-CaP can reverse the MDR of osteosarcoma by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (ABCB1 and ABCC1). Finally, DOX-loaded Se-CaP can significantly inhibit DOX-resistant MG63 (MG63/DXR) tumor growth in nude mice. Considering its biomimetic chemical properties, the Se-CaP biomineral, with the multiple functions mentioned above, could be a promising candidate for treating bone tumors with MDR characteristics.

Is increased symptom interval associated with advanced stage and poorer outcome? A prospective multicenter study of 220 patients with osteosarcoma around the knee.

OBJECTIVE: Osteosarcoma is rare disease and there is a strong controversy about the potential impact of symptom interval on the stage of disease and patients' outcomes. We want to assess whether increased symptom interval (SI) is associated with advanced tumor stage and poor prognosis for patients with osteosarcoma. METHODS: We analyzed prospectively collected data of 220 patients younger than 40 years who had osteosarcoma around the knee. Symptom interval was analyzed to evaluate its impact on metastases at diagnosis, tumor volume, chemotherapy response and overall survival. RESULTS: The median of SI was 64.5 (Q1-Q3: 42-88) days. The 5-year overall survival rate for patients with different length of symptom interval (<42 days, 42-64 days, 65-87 days, > = 88 days) were 0.78 (95 %CI: 0.67-0.89), 0.49 (95 %CI: 0.35-0.63), 0.52 (95 %CI:0.39-0.65), and 0.65 (95 %CI:0.53-0.77) respectively(p = 0.013). Nonparametric test showed increased SI was associated with metastases at diagnosis (p = 0.008), but not associated with large tumor volume or poor chemotherapy response. Cox regression mode test showed that patient with increased SI had higher hazard ratio (42-64 days HR: 2.586 (95 %CI:1.360-4.915); 65-87 days, HR: 2.225 (95 %CI:1.170-4.233)) for poor outcomes compared to short SI (<42 days), though it was not significant in multivariate analysis (p = 0.182). CONCLUSION: Increased SI but not the longest SI is associated with higher incidence of metastases at diagnosis; patients can benefit from an earlier diagnosis in terms of survival.

Comparative study of pronator teres branch transfer and brachialis motor branch transfer to the anterior interosseous nerve to treat lower brachial plexus injury in rats.

Distal nerve transfer is used to treat lower brachial plexus palsy, but outcome series on these transfer procedures following lower plexus injuries are sparse. The objective of this study is to compare treatment outcomes after nerve transfer using the brachialis motor branch (BMB) versus that using the pronator teres motor branch (PTMB). One hundred twenty adult rats with C8T1 nerve root avulsion were randomly divided into three groups (40 each): A: BMB transfer to the anterior interosseous nerve (AIN), B: PTMB transfer to the AIN, and C: no repair. Electrophysiological examination result, muscle tension test result, muscle weight and muscle fiber cross-sectional area of the flexor digitorum profundus and flexor pollicis longus, and number of myelinated nerve fibers in the AIN were compared among the groups to evaluate the treatment outcome. Nerve regeneration and muscle recovery in group B was better than those in group A at 4 and 8 weeks postoperatively (P < 0.05). There was no significant difference in the myelinated nerve fibers in groups A and B at 12 and 16 weeks postoperatively. The rats in group B showed greater and more significant improvement in other measured values than those in group A (P < 0.05). In conclusion, the PTMB seems a better donor nerve than the BMB for distal nerve transfer to treat lower brachial plexus injury according to the electrophysiological and histological examination in this rat study.

Treatment-Related Prognostic Factors in Managing Osteosarcoma around the Knee with Limb Salvage Surgery: A Lesson from a Long-Term Follow-Up Study.

PURPOSE: The aim of this study was to assess the treatment-related factors associated with local recurrence and overall survival of patients with osteosarcoma treated with limb-salvage surgery. PATIENTS AND METHODS: Treatment-related factors were analyzed to evaluate their effects on local recurrence-free survival (LRFS) and overall survival (OS) in 182 patients from 2004 to 2013. RESULTS: The mean length of follow-up was 73.4 ± 34.7 months (median, 68 months; range, 12-173 months), and 63 patients died by the end of the follow-up. The 5-year and 10-year overall survival rates were 68.6 ± 6.6% and 59.4 ± 10.6%, respectively. Univariate analysis showed that treatment-related prognostic factors for overall survival were prolonged symptom intervals >=60 days, biopsy/tumor resection performed by different centers, previous medical history, incomplete preoperative chemotherapy (<8 weeks), and prolonged postoperative interval >21 days. In the multivariate analysis, biopsy/tumor resection performed by different centers, incomplete implementation of planned new adjuvant chemotherapy, and delayed resumption of postoperative chemotherapy (>21 days) were risk factors for poor prognosis; biopsy/tumor resection performed by different centers and tumor necrosis <90% were independent predictors of local recurrence. CONCLUSION: For localized osteosarcoma treated with limb-salvage surgery, it is necessary to optimize timely standard chemotherapy and to resume postoperative chemotherapy to improve survival rates. Biopsies should be performed at experienced institutions in cases of developing local recurrence.

Analyzing the Interactions of mRNAs and ncRNAs to Predict Competing Endogenous RNA Networks in Osteosarcoma Chemo-Resistance.

Chemo-resistance is a huge obstacle encountered in the osteosarcoma (OS) treatment. Protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), including long ncRNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA), have been demonstrated to play an essential role in the regulation of cancer biology. However, the comprehensive expression profile and competing endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in the OS chemo-resistance still remain unclear. In the current study, we developed whole-transcriptome sequencing (RNA sequencing [RNA-seq]) in the three paired multi-drug chemo-resistant and chemo-sensitive OS cell lines to comprehensively identify differentially expressed lncRNAs, circRNAs, miRNAs, and mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for mRNAs with significantly different expression. Then the ceRNA networks combining lncRNAs, circRNAs, miRNAs, and mRNAs were predicted and constructed on the basis of the authoritative miRanda and TargetScan databases combined with the widely accepted vital drug resistance-related genes and signal transduction pathways. In addition, two constructed ceRNA regulatory pathways, lncRNAMEG3/hsa-miR-200b-3p/AKT2 and hsa_circ_0001258/hsa-miR-744-3p/GSTM2, were randomly selected and validated by real-time qPCR, RNA immunoprecipitation (RIP), RNA pull-down assay, and dual luciferase reporter gene system. Taken together, our findings may provide new evidence for the underlying mechanism of OS chemo-resistance and uncover some novel targets for reversing it.

Limb salvage for malignant bone tumours of distal tibia with dual ipsilateral vascularized autogenous fibular graft in a trapezoid-shaped array with ankle arthrodesis and preserving subtalar joint.

BACKGROUND: The treatment of malignant tumours of the distal tibia is a challenging surgical problem due to the scarce soft tissue coverage and the instability of the ankle joint that often occurs after resection. However, there is no consensus on the ideal treatment for malignant tumours of the distal tibia. METHODS: We report a new reconstruction for five patients with high-grade osteosarcoma of distal tibia, using dual ipsilateral vascularized autogenous fibular graft in a trapezoid-shaped array and external fixator, with ankle arthrodesis and preserving subtalar joints. The patients were examined clinically and radiographically. RESULTS: The average follow-up duration was 88 months. The mean wound healing time was 14 days. Bone healing was achieved for all the five patients at an average time of 7 months. There were no complications of mal-union, skin necrosis, post-operative infection, loss of internal fixation, peroneal nerve injury. One patient had a local recurrence, which required amputation 15 months postoperatively. The remaining four patients were able to walk with an average functional score of 81.25% according to MSTS. CONCLUSIONS: Our study shows that this technique is safe and effective to perform implantation of dual ipsilateral vascularized autogenous fibular graft in a trapezoid-shaped array and preserving subtalar joints in terms of the distal tibial reconstruction for malignant bone tumour of the distal tibia. This reconstruction represents a biological alternative protocol for limb salvage in cases of malignant bone tumour of the distal tibia, with encouraging results and with the advantages of lower complications and accelerating recovery. LEVEL OF EVIDENCE: Level IV.

Evodiamine prevents dextran sulfate sodium-induced murine experimental colitis via the regulation of NF-κB and NLRP3 inflammasome.

Evodiamine (EVO), an extraction from the traditional Chinese medicine Evodia rutaecarpa, has been reported to possess anti-inflammatory, anti-tumor and other pharmacological activities. However, the effectiveness of EVO to relieve dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) has not been evaluated. In this study, the protective effects and mechanisms of EVO on DSS-induced UC mice were investigated. The results indicated that treatment with EVO ameliorated DSS-induced UC mice body weight loss, disease activity index (DAI), colon length shortening, colonic pathological damage, and myeloperoxidase (MPO) activity. The production of TNF-α, IL-1ß and IL-6 was also significantly inhibited by EVO. Further mechanistic results showed that EVO restrained the inflammation by regulating NF-κB signal and NLRP3 inflammasome. Furthermore, results also showed that EVO contributed to the tight junction (TJ) architecture integrity by modulating the expression of zonula occludens-1 (ZO-1) and occludin during colitis. Surprisingly, treatment with EVO reduced the concentration of plasmatic lipopolysaccharide (LPS) and re-balanced the levels of Escherichia coli and Lactobacillus. These findings suggested that EVO may have a potential protective effect on DSS-induced colitis and may be useful for the prevention and treatment of UC.

Adverse Radiographic Outcomes Following Operative Treatment of Medial Malleolar Fractures.

BACKGROUND: We initiated a retrospective study on ankle fractures to assess (1) the time needed for fracture union; (2) the incidence of adverse radiographic outcomes (AROs); (3) factors that might lead to AROs; and (4) whether AROs were associated with worse function and higher incidence of post-trauma osteoarthritis (PTOA). METHODS: From 2007 to 2016, a total of 296 patients (169 women, 127 men; average age, 48.6 years; range, 20-84) were diagnosed with a medial malleolar fracture, whether isolated or in the setting of bi- or trimalleolar fractures, and underwent open reduction and internal fixation (ORIF) or percutaneous screw fixation (PSF). The interval to fracture union, radiographic outcomes, American Orthopaedic Foot & Ankle Society (AOFAS) score at 6 months postoperatively, and the incidence of PTOA were recorded. Risk factors were identified both in univariate and multivariate analysis. The average follow-up period was 52.0 months (range, 12-118). RESULTS: The incidence of delayed union, nonunion, and malunion were 20.3%, 3.7%, and 4.4%, respectively. The interval to fracture union was 10.3 ± 6.4 weeks. In the multivariate analysis, the risk factors for AROs were tobacco use, vertical fractures, interposed soft tissue, and fair/poor reduction. Patients with AROs had significantly worse AOFAS score at 6 months postoperatively ( P < .001) and higher incidence of PTOA ( P < .001). CONCLUSION: AROs of medial malleolar fractures have an underestimated incidence rate and are associated with worse ankle function and higher incidence of PTOA. Risk factors including tobacco use, vertical fractures, interposed soft tissue, poor/fair reduction should be prudently taken into consideration when treating medial malleolar fractures. LEVEL OF EVIDENCE: Level III, retrospective cohort study.