Bioactive 3D Electrohydrodynamic Printed Lattice Architectures Augment Tenogenesis of Tendon Stem/Progenitor Cells.

Tendon defect repair remains a tough clinical procedure that hinders functional motion in patients. Electrohydrodynamic (EHD) three-dimensional (3D) printing, as a novel strategy, can controllably fabricate biomimetic micro/nanoscale architecture, but the hydrophobic and bioinert nature of polymers might be adverse to cell-material interplay. In this work, 3D EHD printed polycaprolactone (PCL) was immobilized on basic fibroblast growth factor (bFGF) using polydopamine (PDA), and the proliferation and tenogenic differentiation of tendon stem/progenitor cells (TSPCs) in vitro was researched. A subcutaneous model was established to evaluate the effects of tenogenesis and immunomodulation. We then investigated the in situ implantation and immunomodulation effects in an Achilles tendon defect model. After immobilization of bFGF, the scaffolds profoundly facilitated proliferation and tenogenic differentiation; however, PDA had only a proliferative effect. Intriguingly, the bFGF immobilized on EHD printed PCL indicated a synergistic effect on the highest expression of tenogenic gene and protein markers at 14 days, and the tenogenesis may be induced by activating the transforming growth factor-ß (TGF-ß) signal pathway in vitro. The subcutaneous engraftment study confirmed a tendon-like structure, similar to that of the native tendon, as well as an M2 macrophage polarization effect. Additionally, the bioactive scaffold exhibited superior efficacy in new collagen formation and repair of Achilles tendon defects. Our study revealed that the topographic cues alone were insufficient to trigger tenogenic differentiation, requiring appropriate chemical signals, and that appropriate immunomodulation was conducive to tenogenesis. The tenogenesis of TSPCs on the bioactive scaffold may be correlated with the TGF-ß signal pathway and M2 macrophage polarization.

A deep learning model for accurately predicting cancer-specific survival in patients with primary bone sarcoma of the extremity: a population-based study

Purpose Primary bone and joint sarcomas of the long bone are relatively rare neoplasms with poor prognosis. An efficient clinical tool that can accurately predict patient prognosis is not available. The current study aimed to use deep learning algorithms to develop a prediction model for the prognosis of patients with long bone sarcoma. Methods Data of patients with long bone sarcoma in the extremities was collected from the Surveillance, Epidemiology, and End Results Program database from 2004 to 2014. Univariate and multivariate analyses were performed to select possible prediction features. DeepSurv, a deep learning model, was constructed for predicting cancer-specific survival rates. In addition, the classical cox proportional hazards model was established for comparison. The predictive accuracy of our models was assessed using the C-index, Integrated Brier Score, receiver operating characteristic curve, and calibration curve. Results Age, tumor extension, histological grade, tumor size, surgery, and distant metastasis were associated with cancer-specific survival in patients with long bone sarcoma. According to loss function values, our models converged successfully and effectively learned the survival data of the training cohort. Based on the C-index, area under the curve, calibration curve, and Integrated Brier Score, the deep learning model was more accurate and flexible in predicting survival rates than the cox proportional hazards model. Conclusion A deep learning model for predicting the survival probability of patients with long bone sarcoma was constructed and validated. It is more accurate and flexible in predicting prognosis than the classical CoxPH model (AU)

Downregulation of salusins alleviates hypertrophic cardiomyopathy via attenuating oxidative stress and autophagy.

INTRODUCTION: Salusins, which are translated from the alternatively spliced mRNA of torsin family 2 member A (TOR2A), play a vital role in regulation of various cardiovascular diseases. However, it remains unclear precisely regarding their roles in hypertrophic cardiomyopathy (HCM). Therefore, this study was conducted to explore therapeutic effect and the underlying mechanisms of salusins on HCM. MATERIAL AND METHODS: In vivo experiments, Sprague-Dawley rats were used to induce HCM model by angiotensin (Ang) II infusion for 4 weeks. The rats were randomly divided into four groups, namely, Saline + Control shRNA (n = 7), Ang II + Control shRNA (n = 8), Saline + TOR2A shRNA (n = 7), and Ang II + TOR2A shRNA groups (n = 8). After HCM induction, doppler echocardiography is recommended to evaluate heart function. In vitro experiments, primary neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (NRCFs) were obtained from newborn rats, and were treated with Ang II (10-6 M) for 24 h. RESULTS: After treatment with Ang II, levels of salusin-α and salusin-ß were elevated in serum and cardiac tissues of rats and in the neonatal rat cardiomyocytes and cardiac fibroblasts. Downregulation of salusins alleviated the Ang II-induced cardiac hypertrophy by suppressing the increased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (ß-MHC) and cardiac fibrosis by blocking collagen I, collagen III and transforming growth factor-beta (TGF-ß), and it also attenuated oxidative stress by suppressing the increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels and reversing the decreased superoxide dismutase (SOD) activity and autophagy by inhibiting the increased microtubule-associated protein light chain 3B (LC3B), Beclin1, autophagy related gene (Atg) 3 and Atg5 in the cardiac tissues of Ang II-infused rats and in the Ang II-treated NRCMs. CONCLUSIONS: All these findings suggest that the levels of salusins were elevated in the HCM, and targeting of salusins contributes to alleviation of cardiac hypertrophy and fibrosis probably via attenuating oxidative stress and autophagy. Accordingly, targeting of salusins may be a strategy for HCM therapy.

Calcium phosphate coating enhances osteointegration of melt electrowritten scaffold by regulating macrophage polarization.

The osteoimmune microenvironment induced by implants plays a significant role in bone regeneration. It is essential to efficiently and timely switch the macrophage phenotype from M1 to M2 for optimal bone healing. This study examined the impact of a calcium phosphate (CaP) coating on the physiochemical properties of highly ordered polycaprolactone (PCL) scaffolds fabricated using melt electrowritten (MEW). Additionally, it investigated the influence of these scaffolds on macrophage polarization and their immunomodulation on osteogenesis. The results revealed that the CaP coated PCL scaffold exhibited a rougher surface topography and higher hydrophilicity in comparison to the PCL scaffold without coating. Besides, the surface morphology of the coating and the release of Ca2+ from the CaP coating were crucial in regulating the transition of macrophages from M1 to M2 phenotypes. They might activate the PI3K/AKT and cAMP-PKA pathways, respectively, to facilitate M2 polarization. In addition, the osteoimmune microenvironment induced by CaP coated PCL could not only enhance the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) in vitro but also promote the bone regeneration in vivo. Taken together, the CaP coating can be employed to control the phenotypic switching of macrophages, thereby creating a beneficial immunomodulatory microenvironment that promotes bone regeneration.

A deep learning model for accurately predicting cancer-specific survival in patients with primary bone sarcoma of the extremity: a population-based study.

PURPOSE: Primary bone and joint sarcomas of the long bone are relatively rare neoplasms with poor prognosis. An efficient clinical tool that can accurately predict patient prognosis is not available. The current study aimed to use deep learning algorithms to develop a prediction model for the prognosis of patients with long bone sarcoma. METHODS: Data of patients with long bone sarcoma in the extremities was collected from the Surveillance, Epidemiology, and End Results Program database from 2004 to 2014. Univariate and multivariate analyses were performed to select possible prediction features. DeepSurv, a deep learning model, was constructed for predicting cancer-specific survival rates. In addition, the classical cox proportional hazards model was established for comparison. The predictive accuracy of our models was assessed using the C-index, Integrated Brier Score, receiver operating characteristic curve, and calibration curve. RESULTS: Age, tumor extension, histological grade, tumor size, surgery, and distant metastasis were associated with cancer-specific survival in patients with long bone sarcoma. According to loss function values, our models converged successfully and effectively learned the survival data of the training cohort. Based on the C-index, area under the curve, calibration curve, and Integrated Brier Score, the deep learning model was more accurate and flexible in predicting survival rates than the cox proportional hazards model. CONCLUSION: A deep learning model for predicting the survival probability of patients with long bone sarcoma was constructed and validated. It is more accurate and flexible in predicting prognosis than the classical CoxPH model.

Effect and mechanism of circHMGA2 on ferroptosis and pyroptosis in myocardial ischemia-reperfusion model CircHMGA2 exacerbates MI/R injury.

Myocardial ischemia-reperfusion (MI/R) injury is a common and serious complication following reperfusion treatment for myocardial infarction (MI). Increasing evidence has verified the crucial role of circular RNAs (circRNAs) in the MI/R injury processes. The objective of this study was to investigate the effects and potential regulatory mechanisms of circHMGA2 on MI/R injury. Hypoxia/reoxygenation (H/R) models were established using human cardiac myocytes (HCMs) and mice models were induced by MI/R. The level of circHMGA2 was detected by RT-qPCR. Myocardial function was evaluated by the hemodynamic parameters, the activity of serum myocardial enzymes, HE staining and TUNEL assays. Cell proliferation was measured by CCK-8 assay. The ferrous ion (Fe2+) level was determined with an iron assay kit. Ferroptosis- and pyroptosis-related proteins were determined using western blotting. The levels of oxidative stress and inflammatory factors were analyzed using DCFH-DA staining or ELISA assays. CircHMGA2 was upregulated in H/R-induced HCMs and myocardial tissues of MI/R mice. In vitro, circHMGA2 knockdown attenuated the proliferation inhibition, restrained the ferroptosis and pyroptosis in H/R-induced HCMs. This regulatory mechanism may be associated with the suppression of NLRP3 pathway. In vivo, circHMGA2 depletion attenuated myocardial tissue damage of MI/R mice through inhibiting the oxidative stress and pyroptosis. Taken together, CircHMGA2 enhanced MI/R injury via promoting ferroptosis and pyroptosis, providing new insights into the treatment of MI/R injury.

Using network pharmacology to fabricate crosslinked hyaluronan-chondroitin sulphate-resveratrol composite hydrogels for cartilage regeneration.

Cartilage tissue engineering provides a new approach for the treatment of cartilage damage. The combination of drug system with a tissue scaffold could be highly beneficial. Resveratrol (RES) is a potent anti-inflammatory agent, but its target genes and molecular mechanism of cartilage repair remain to be further studied. We used systems biology and network pharmacology methods to explore the mechanism of RES for chondrocyte and macrophages. Meanwhile, crosslinked hyaluronan-chondroitin sulphate-RES hydrogels (cHA-CS-RES) were constructed based on the target prediction results. Byin vitroandin vivoexperiments, we investigated its anti-inflammatory and pro-chondrogenesis. The results showed there were 12 hub genes potentially interacting in the RES-chondrocyte-macrophage network.In vitroexperiments were used to further verify the validity of the predicted hub genes. The composite hydrogels were successfully fabricated, and maintenance of the characteristic was further confirmed.In vitrostudy, cHA-CS-RES showed high cell viability, anti-inflammatory and pro-chondrogenesis abilities.In vivostudy of cartilage defects confirmed that the cHA-CS-RES groups were significantly better than the control group. Network pharmacology was used to predict and screen the target proteins of RES critical to cartilage tissue engineering. Moreover, cHA-CS-RES composite hydrogel showed good cartilage repair effects, anti-inflammatory and pro-chondrogenesis abilities.

Identification of key biomarkers related to epithelial-mesenchymal transition and immune infiltration in ameloblastoma using integrated bioinformatics analysis.

OBJECTIVE: This study aimed to elucidate the underlying mechanisms of ameloblastoma (AM) through integrated bioinformatics analysis. METHODS: We downloaded two microarrays of AMs from the GEO database and identified differentially expressed genes (DEGs) by integrated bioinformatics analysis. The enrichment analysis of DEGs was conducted to characterize GO and KEGG pathways. Protein-protein interaction (PPI) network and hub genes were screened via STRING and Cytoscape. CIBERSORT algorithm was utilized to analyze immune infiltration in AMs. We also verified the diagnostic and therapeutic value of hub genes. RESULTS: Overall, 776 DEGs were identified in AMs through bioinformatics analysis. The function enrichment analysis shed light on pathways involved in AMs. Subsequently, we screened six hub genes via PPI network. Furthermore, we evaluated immune infiltration in AMs and found that macrophages may be participating in the progression of AMs. The upregulated expression of FN1 was related to the macrophages M2 polarization. Finally, ROC analysis indicated that six hub genes had high diagnostic value for AMs and 11 drugs interacted with upregulated hub genes were identified by screening the DGIdb database. CONCLUSION: This study revealed the underlying mechanisms of pathogenesis and biological behavior of AMs and provided candidate targets for the diagnosis and treatment of AMs.

Characterization of myeloid signature genes for predicting prognosis and immune landscape in Ewing sarcoma.

Myeloid cells as a highly heterogeneous subpopulation of the tumor microenvironment (TME) are intimately associated with tumor development. Ewing sarcoma (EWS) is characterized by abundant myeloid cell infiltration in the TME. However, the correlation between myeloid signature genes (MSGs) and the prognosis of EWS patients was unclear. In this research, we synthetically characterized the expression of MSGs in a training cohort and classified EWS patients into two subtypes. Immune cell infiltration analysis revealed that MSGs subtypes correlated closely with different immune statuses. Furthermore, a three-gene prognostic model (CTSD, SIRPA, and FN1) was constructed by univariate, LASSO, and multivariate Cox analysis, and it showed excellent prognostic accuracy in EWS patients. We also developed a nomogram for better predicting the long-term survival of EWS. Functional enrichment analysis showed immune-related pathways were distinctly different in the high- and low-risk groups. Further analysis revealed that patients in the high-risk group were tightly associated with an immunosuppressive microenvironment. Finally, we validated the expression of these candidate genes by Western blot (WB), qPCR, and immunohistochemistry (IHC) analysis. To sum up, our study identified that the MSGs model was strongly linked to prognostic prediction and immune infiltration in EWS patients, providing novel insights into the clinical treatment and management of EWS patients.

Customized three dimensional printed prosthesis as a novel intercalary reconstruction for resection of extremity bone tumours: a retrospective cohort study.

AIMS: The 3D-printed prosthesis (3DP) is a novel treatment for massive bone defect reconstruction after tumor resection. This study was aiming to explore the clinical efficacy of customized 3DP for intercalary reconstruction by comparing the clinical outcomes after implanting customized 3DP or conventional allograft in limb salvage surgery. METHODS: A total of 28 patients with extremity bone tumors who underwent customized 3DP or conventional allograft reconstruction between 2011 and 2018 at our institution were analyzed retrospectively. Among them, 14 cases received customized 3DP reconstruction (3DP group), and 14 cases received conventional allograft reconstruction (control group). Demographics, surgical outcomes, radiographical assessments, limb functions, and post-operative complications between these two groups were collected to evaluate clinical outcomes. RESULTS: No significant difference was observed in the demographics, mean intra-operative blood loss, MOSI scores, and MSTS scores between the two groups. Patients in 3DP group had a shorter operative time (157.9 vs 199.6 min, p = 0.03) and lesser number of fluoroscopy (4.1 vs 8.1, p < 0.001) compared to control group. The mean time to osseointegration at bone-implant interfaces in 3DP group was significantly earlier than that in control group (6.1 vs 12.2 months, p < 0.001). Moreover, the 3DP group had a significantly lower post-operative complication rate than the control group (7% vs 50%, p = 0.03). CONCLUSIONS: The customized 3DP might provide a promising strategy for intercalary reconstruction in limb salvage surgery with more precise reconstruction, higher surgical efficiency, and comparable satisfactory clinical outcomes.

Effect of electrohydrodynamic printing scaffold with different spacing on chondrocyte dedifferentiation.

Background: Osteoarthritis (OA) is a common degenerative disease. Chondrocyte dedifferentiation can accelerate the progress of OA. Three-dimensional printing (3DP) is widely used in tissue regeneration applications. A three-dimensional (3D) culture system with 3D printed scaffolds could reduce the dedifferentiation of chondrocytes during passages, which would be a potential method for chondrocyte expansion. Methods: The viability and proliferation of chondrocytes on scaffolds and effects of scaffolds with 100, 150, 200, 250 or 300 µm spacing on chondrocyte dedifferentiation were analyzed in vitro. The morphology of scaffolds and cell/scaffold constructs was observed by scanning electron microscopy (SEM). Glycosaminoglycan (GAG) was evaluated by Alcian blue staining. The effects of different spacing on chondrocyte dedifferentiation were evaluated by the messenger RNA (mRNA) and protein levels of cartilage-related genes. Results: With more binding sites, the proliferation and viability of chondrocytes on scaffolds with 100 and 150 µm spacing were better than those with 200, 250 and 300 µm spacing on day 1, but this advantage diminished over time. The histology and quantitative real-time polymerase chain reaction (qRT-PCR) results showed that 200 µm spacing inhibits chondrocyte dedifferentiation better. Conclusions: 3D printed scaffolds with 200 µm spacing can inhibit chondrocyte dedifferentiation, providing a basis for the future study of 3D printed scaffolds as an effective method for chondrocyte expansion.

Unfolded Protein Response-Related Signature Associates With the Immune Microenvironment and Prognostic Prediction in Osteosarcoma.

Background: Osteosarcoma is a highly malignant bone tumor commonly occurring in adolescents with a poor 5-year survival rate. The unfolded protein response (UPR) can alleviate the accumulation of misfolded proteins to maintain homeostasis under endoplasmic reticulum stress. The UPR is linked to the occurrence, progression, and drug resistance of tumors. However, the function of UPR-related genes (UPRRGs) in disease progression and prognosis of osteosarcoma remains unclear. Methods: The mRNA expression profiling and corresponding clinical features of osteosarcoma were acquired from TARGET and GEO databases. Consensus clustering was conducted to confirm different UPRRG subtypes. Subsequently, we evaluated the prognosis and immune status of the different subtypes. Functional analysis of GO, GSEA, and GSVA was used to reveal the molecular mechanism between the subtypes. Finally, four genes (STC2, PREB, TSPYL2, and ATP6V0D1) were screened to construct and validate a risk signature to predict the prognosis of patients with osteosarcoma. Result: We identified two subtypes according to the UPRRG expression patterns. The subgroup with higher immune scores, lower tumor purity, and active immune status was linked to a better prognosis. Meanwhile, functional enrichment revealed that immune-related signaling pathways varied markedly in the two subtypes, suggesting that the UPR might influence the prognosis of osteosarcoma via influencing the immune microenvironment. Moreover, prognostic signature and nomogram models were developed based on UPRRGs, and the results showed that our model has an excellent performance in predicting the prognosis of osteosarcoma. qPCR analysis was also conducted to verify the expression levels of the four genes. Conclusion: We revealed the crucial contribution of UPRRGs in the immune microenvironment and prognostic prediction of osteosarcoma patients and provided new insights for targeted therapy and prognostic assessment of the disease.

[Biomechanical analysis and effectiveness evaluation of zone â +â ¡+â ¢ reconstruction of hemipelvis with rod-screw prosthesis].

Objective: To analyze the biomechanical properties of the rod-screw prosthesis based on a pelvic three-dimensional finite element model including muscle and ligament, and evaluate the effectiveness of zoneⅠ+Ⅱ+Ⅲ reconstruction of hemipelvis with rod-screw prosthesis in combination with clinical applications. Methods: A total of 21 patients who underwent hemipelvic tumor resection (zoneⅠ+Ⅱ+Ⅲ) and rod-screw prosthesis reconstruction between January 2015 and December 2020 were selected as the research subjects. Among them, there were 11 males and 10 females; the age ranged from 16 to 64 years, with an average age of 39.2 years. There were 9 cases of chondrosarcoma, 7 cases of osteosarcoma, 3 cases of Ewing sarcoma, and 2 cases of undifferentiated pleomorphic sarcoma. According to the Musculoskeletal Tumor Society Score (MSTS) staging, there were 19 cases of stage ⅡB and 2 cases of stage Ⅲ. Preoperative Harris Hip Score (HHS) and MSTS score were 54.4±3.1 and 14.1±2.0, respectively. Intraoperative 15 cases underwent extensive resection, 5 cases underwent marginal resection, and 1 case underwent intralesional resection. The CT image of 1 patient after reconstruction was used to establish a three-dimensional solid model of the pelvis via Mimics23Suite and 3-matic softwares. At the same time, a mirror operation was used to obtain a normal pelvis model, then the two solid models were imported into the finite element analysis software Workbench 2020R1 to establish three-dimensional finite element models, and the biomechanical properties of the standing position were analyzed. The operation time, intraoperative blood loss, and operation-related complications were recorded, and the postoperative evaluation was carried out with HHS and MSTS scores. Finally, the local recurrence and metastasis were reviewed. Results: Finite element analysis showed that the peak stress of the reconstructed pelvis appeared at the fixed S1, 2 rod-screw connections; the peak stress without muscles was higher than that after muscle construction, but much smaller than the yield strength of titanium alloy. The operation time was 250-370 minutes, with an average of 297 minutes; the amount of intraoperative blood loss was 3 200-5 500 mL, with an average of 4 009 mL. All patients were followed up 8-72 months, with an average of 42 months. There were 7 cases of pulmonary metastasis, of which 2 cases were preoperative metastasis; 5 cases died, 16 cases survived, and the 5-year survival rate was 72.1%. There were 3 cases of local recurrence, all of whom did not achieve extensive resection during operation. The function of the affected limbs significantly improved, and the walking function was restored. The HHS and MSTS scores were 75.2±3.0 and 20.4±2.0 at last follow-up, respectively, and the differences were significant when compared with those before operation (t=22.205, P<0.001; t=11.915, P<0.001). During follow-up, 2 cases of delayed incision healing, 2 cases of deep infection, 1 case of screw loosening, and 1 case of prosthesis dislocation occurred, and no other complication such as prosthesis or screw fracture occurred. Conclusion: The stress and deformation distribution of the reconstructed pelvis are basically the same as normal pelvis. The rod-screw prosthesis is an effective reconstruction method for pelvic malignant tumors.

Clinical application of 3D-printed patient-specific guide plate combined with computer navigation in acetabular reconstruction following resection of periacetabular tumors.

Background: The precise acetabular reconstruction has historically been a challenging procedure. 3D-printed patient-specific guide (PSG) and computer navigation (CN) technologies have been used to assist acetabular component positioning and pelvic reconstruction. This precise reconstruction approach may translate into clinical benefit. Methods: The clinical data of 84 patients who underwent periacetabular malignant tumor resection and screw-rod-acetabular cage system reconstruction in our center from January 2013 to December 2020 were retrospectively analyzed. Patients were divided into four groups: free hand (FH) group, PSG group, CN group, and PSG combined with computer navigation (PSG + CN) group. The operation time, intraoperative blood loss, and number of fluoroscopy views were recorded. The oncological prognosis, radiographic measurements of the acetabulum, limb function data, and postoperative complications were compared among groups. And finally, we evaluated the risk factors for mechanical failure of the prosthesis. Results: The postoperative X-ray and computed tomography (CT) scan revealed that the vertical offset discrepancy (VOD) between affected side and contralateral side was 8.4±1.9, 5.9±2.2, 4.1±1.3, and 2.4±1.2 mm in each groups; the horizontal offset discrepancy (HOD) was 9.0±1.9, 6.1±2.2, 3.2±1.3, and 2.1±1.2 mm, correspondingly; the abduction angle discrepancy (ABAD) was 8.6°±1.8°, 5.6°±2.0°, 2.5°±1.3°, and 1.8°±0.9°, respectively; the anteversion angle discrepancy (ANAD) was 5.9°±1.6°, 3.6°±1.7°, 2.9°±1.6°, and 1.9°±0.9°, correspondingly. Statistical results show that the PSG + CN group was superior to the FH group and the PSG group in terms of acetabular position and limb function (P<0.05). Body mass index (P=0.040) and resection type (P=0.042) were found to be the high-risk factors for mechanical failure of the prosthesis. Conclusions: PSG + CN has potential advantages in improving the accuracy and safety of acetabular positioning and reconstruction.

Investigating the protective effect of tanshinone IIA against chondrocyte dedifferentiation: a combined molecular biology and network pharmacology approach.

BACKGROUND: Osteoarthritis (OA) is a common degenerative disease with multifactorial etiology. The dedifferentiation of chondrocytes can accelerate the progress of OA. Tanshinone IIA (TIIA) has been widely used to treat OA for many years and has proved to be effective in inhibiting chondrocyte dedifferentiation. Until now, the precise mechanism of TIIA's effect against dedifferentiation has not been well understood. METHODS: The targets of TIIA were explored from public databases using various methods. The related targets of OA were obtained from the GeneCards database and the Online Mendelian Inheritance in Man (OMIM) database. The potential targets and signaling pathways were determined using protein-protein interaction (PPI), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Cell viability, proliferation, and metabolic activity were analyzed in vitro. The effects of TIIA on chondrocyte dedifferentiation were evaluated by assessing morphological changes, glycosaminoglycan (GAG) production, and messenger RNA (mRNA) levels of cartilage-related genes. After 48 hours of culture in medium with 100 µg/mL TIIA, chondrocytes/hydrogel spheres were implanted to repair cartilage defects in a rat model. The harvested specimens were examined with hematoxylin and eosin (H&E) staining and immunohistochemistry to evaluate cartilage regeneration. RESULTS: The results showed that there were 28 genes potentially interacting in the TIIA-chondrocyte dedifferentiation network, and nine hub genes were identified. In vitro experiments showed an inhibitory effect of TIIA on chondrocyte dedifferentiation. The proliferation and viability of chondrocytes were promoted by TIIA at a concentration of 100-200 µg/mL, but inhibited by TIIA at 400 µg/mL. Furthermore, the histology results showed that chondrocyte/hydrogel spheres pre-treated with TIIA had better cartilage repair. CONCLUSIONS: This study revealed a systematic network pharmacology approach and provided a basis for the future study of TIIA as an effective treatment for cartilage regeneration. Moreover, in vitro and in vivo results confirmed the protective effects of TIIA against chondrocyte dedifferentiation.

Comparison between trabectedin and doxorubicin in soft-tissue sarcomas: a systematic review and meta-analysis.

BACKGROUND: This study sought to evaluate the differences between trabectedin and doxorubicin in the treatment of soft-tissue sarcoma (STS). METHODS: Multiple databases, including PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure, were searched to retrieve relevant articles. Ultimately, the full text of 10 studies involving the use of trabectedin and doxorubicin in STS were reviewed. Review Manager 5.2 was used to evaluate the heterogeneity of the results of the selected articles. Forest plot, bias, and sensitivity analyses were carried out on the included articles. RESULTS: Ten papers that met the criteria were included in this analysis. STS patients receiving trabectedin had longer progression-free survival than those receiving doxorubicin [overall mean difference (MD) =1.36, 95% confidence interval (CI): 1.04, 1.68, I2=6%, fixed-effects model]. The experimental group also had a longer overall survival period than the control group (MD =3.92, 95% CI: 0.23, 7.60, P=0.04 and I2=83%, random-effects model), and the experimental group had a better disease control rate than the control group (relative risk =1.2, P=0.03 and I2=45%, fixed-effects model). From the publication bias analysis and sensitivity analysis, we can guarantee the results are robust and unbiased. DISCUSSION: Our research showed that STS patients who received trabectedin had better clinical effects and a longer survival time than those who received doxorubicin.