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Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. Therapeutic targeting of osteosarcoma has been unsuccessful; therefore, identifying novel osteosarcoma pathogenesis could offer new therapeutic options. CDK7 is a subunit within the general transcription factor TFIIH. We aim to explore the new mechanism by which CDK7 regulates osteosarcoma and our studies may provide new theoretical support for the use of CDK7 inhibitors in the treatment of osteosarcoma. Here, we investigate the molecular mechanism underlying the association between CDK7 and GRP78 in osteosarcoma. Specifically, we find that an E3 ubiquitin ligase TRIM21 binds and targets GRP78 for ubiquitination and degradation, whereas CDK7 phosphorylates GRP78 at T69 to inhibit TRIM21 recruitment, leading to GRP78 stabilization. Notably, a CDK7-specific inhibitor, THZ1, blunts osteosarcoma growth and metastasis. Combination treatment with CDK7 and GRP78 inhibitors yield additive effects on osteosarcoma growth and progression inhibition. Thus, simultaneous suppression of CDK7 and GRP78 activity represents a potential new approach for the treatment of osteosarcoma. In conclusion, the discovery of this previously unknown CDK7/GRP78 signaling axis provides the molecular basis and the rationale to target human osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor that most commonly affects children, adolescents, and young adults. Here, we comprehensively analyze genomic, epigenomic and transcriptomic data from 121 OS patients. Somatic mutations are diverse within the cohort, and only TP53 is significantly mutated. Through unsupervised integrative clustering of the multi-omics data, we classify OS into four subtypes with distinct molecular features and clinical prognosis: (1) Immune activated (S-IA), (2) Immune suppressed (S-IS), (3) Homologous recombination deficiency dominant (S-HRD), and (4) MYC driven (S-MD). MYC amplification with HR proficiency tumors is identified with a high oxidative phosphorylation signature resulting in resistance to neoadjuvant chemotherapy. Potential therapeutic targets are identified for each subtype, including platinum-based chemotherapy, immune checkpoint inhibitors, anti-VEGFR, anti-MYC and PARPi-based synthetic lethal strategies. Our comprehensive integrated characterization provides a valuable resource that deepens our understanding of the disease, and may guide future clinical strategies for the precision treatment of OS.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, with highly aggressive behavior and early systemic metastasis. The survival rates for osteosarcoma remain unchanged over the past two decades. Studies aiming to find new or alternative therapies for patients with refractory osteosarcoma are urgently needed. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging clinical activity in NSLCC and soft tissue sarcoma, whereas its effect on osteosarcoma has not been studied. In our study, we investigated the anti-tumor activity and underlying mechanism of anlotinib in osteosarcoma. Various in vitro and in vivo models of human osteosarcoma were used to determine the anti-proliferative, anti-angiogenesis and anti-metastasis efficacy of anlotinib. Our results showed that anlotinib suppressed tumor growth and increased the chemo-sensitivity of osteosarcoma. In addition, anlotinib inhibited migration and invasion in osteosarcoma cells. Furthermore, in order to explore the anti-tumor mechanism of anlotinib, phospho-RTK antibody arrays were performed. These analyses confirmed that anlotinib suppressed the phosphorylation of MET, VEGFR2 and the downstream signaling pathway activation. Moreover, we demonstrated that anlotinib blocked hepatocyte growth factor (HGF)-induced cell migration, invasion and VEGF-induced angiogenesis. Notably, a 143B-Luc orthotopic osteosarcoma model further showed that anlotinib significantly inhibited growth and lung metastasis of implanted tumor cells. Our preclinical work indicates that anlotinib acts as a novel inhibitor of VEGFR2 and MET that blocks tumorigenesis in osteosarcoma, which could be translated into future clinical trials.

Purpose Osteosarcoma is the most common primary bone cancer and is notorious for pulmonary metastasis, representing a major threat to pediatric patients. An effective drug targeting osteosarcoma and its lung metastasis is urgently needed. Design In this study, a sarcoma-targeting peptide-decorated disulfide-crosslinked polypeptide nanogel (STP-NG) was exploited for enhanced intracellular delivery of shikonin (SHK), an extract of a medicinal herb, to inhibit osteosarcoma progression with minimal systemic toxicity. Results The targeted, loaded nanogel, STP-NG/SHK, killed osteosarcoma cells by inducing RIP1- and RIP3-dependent necroptosis in vitro. Necroptosis is a novel cell death form that could be well adapted as an efficient antitumor strategy, the main obstacle of which is its high toxicity. After intravenous injection, STP-NG/SHK efficiently suppressed tumor growth and reduced pulmonary metastasis, offering greater tumor necrosis and higher RIP1 and RIP3 upregulation compared to free SHK or untargeted NG/SHK in vivo. Additionally, the treatment with NG/SHK or STP-NG/SHK showed minimal toxicity to normal organs, suggesting low systemic toxicity compared to free SHK. Conclusion The STP-guided intracellular drug delivery system using the necroptosis mechanism showed profound anti-osteosarcoma activity, especially eliminated lung metastasis in vivo. This drug formulation may have great potential for treatment of osteosarcoma.

Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Arsenic sulfide (As2S2), the main active ingredient of the traditional Chinese medicine realgar, has been proved to have antitumor efficacy in several tumor types including acute promyelocytic leukemia, gastric cancer and colon cancer. Here, we investigated the efficacy and mechanism of As2S2 in osteosarcoma both in vitro and in vivo. In this study, we demonstrated that As2S2 potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with As2S2 induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, -8, -9. As2S2 was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that As2S2-induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that As2S2 inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase As2S2-induced apoptosis and autophagy. Finally, As2S2in vivo suppressed tumor growth with few side effects. In summary, our results revealed that As2S2 induced G2/M phase arrest, apoptosis, and autophagy via activing ROS/JNK and blocking Akt/mTOR signaling pathway in human osteosarcoma cells. Arsenic sulfide may be a potential clinical antitumor drugs targeting osteosarcoma.

Osteosarcoma is the most common primary bone cancer and is notorious for pulmonary metastasis, representing a major threat to pediatric patients. An effective drug targeting osteosarcoma and its lung metastasis is urgently needed.In this study, a sarcoma-targeting peptide-decorated disulfide-crosslinked polypeptide nanogel (STP-NG) was exploited for enhanced intracellular delivery of shikonin (SHK), an extract of a medicinal herb, to inhibit osteosarcoma progression with minimal systemic toxicity.The targeted, loaded nanogel, STP-NG/SHK, killed osteosarcoma cells by inducing RIP1- and RIP3-dependent necroptosisThe STP-guided intracellular drug delivery system using the necroptosis mechanism showed profound anti-osteosarcoma activity, especially eliminated lung metastasis

Osteosarcoma (OS) is the most frequent primary malignant bone tumour. Alternol, a novel compound purified from microbial fermentation products exerts anti‐tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti‐tumour effect of alternol in several human OS cell lines in vitro and investigated its underlying mechanism. Alternol inhibited OS cell proliferation, migration and induced caspase‐dependent apoptosis, G2/M cell cycle arrest in a dose and time‐dependent manner. Moreover, alternol treatment inhibited signal transducer and activator of transcription‐3 (STAT3) phosphorylation in 143B and MG63 human OS cells, as evaluated using a STAT3‐dependent dual luciferase reporter system. Exposure to alternol resulted in excessive reactive oxygen species (ROS) generation and Jun amino‐terminal kinases (JNK), extracellular signal‐regulated kinases (ERK1/2) and p38 activation. Furthermore, alternol‐induced cell death was significantly restored in the presence of the ROS scavenger, N‐acetyl‐l‐cysteine (NAC) or a caspase inhibitor Z‐VAD‐FMK. NAC also prevented G2/M phase arrest and phosphorylation of mitogen‐activated protein kinases (MAPK), but did not reverse STAT3 inactivation. Finally, alternol suppressed tumour growth in vivo in the nude mouse OS tibia orthotopic model. Immunohistochemistry revealed that alternol treatment resulted in down‐regulation of phosph‐STAT3 Tyr705 and up‐regulation of cleaved caspase‐3 and phosph‐SAPK (Stress‐activated protein kinases)/JNK expression. Taken together, our results reveal that alternol suppresses cell proliferation, migration and induces apoptosis, cell cycle arrest by modulating of ROS‐dependent MAPK and STAT3 signalling pathways in human OS cells. Therefore, alternol is a promising candidate for developing anti‐tumour drugs target OS.

// Zhuoying Wang 1, * , Chongren Wang 1, * , Zifei Zhou 1, * , Mengxiong Sun 1 , Chenghao Zhou 2 , Jian Chen 2 , Fei Yin 2 , Hongsheng Wang 2 , Binhui Lin 1 , Dongqing Zuo 2 , Suoyuan Li 2 , Lijin Feng 3 , Zhenfeng Duan 4 , Zhengdong Cai 1, 2 , Yingqi Hua 1, 2 1 Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China 2 Shanghai Bone Tumor Institution, Shanghai, 201620, China 3 Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China 4 Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA * These authors have contributed equally to this work Correspondence to: Zhengdong Cai, email: czd856@vip.163.com Yingqi Hua, email: hua_yingqi@163.com Keywords: osteosarcoma, tetraspanin, CD151, metastasis, adhesion Received: December 25, 2015 Accepted: July 26, 2016 Published: August 19, 2016 ABSTRACT CD151, a tetraspanin family protein involved in cell-cell and cell-extracellular matrix interaction, is differentially expressed in osteosarcoma cell membranes. Thus, this study aimed to investigate the role of CD151 in osteosarcoma metastasis. We analyzed CD151 expression in patient tissue samples using immunohistochemistry. CD151 expression was also silenced with shRNA in osteosarcoma cells of high metastatic potential, and cell adhesion, migration and invasion were evaluated in vitro and pulmonary metastasis was investigated in vivo . Mediators of cell signaling pathways were also examined following suppression of CD151 expression. Overall survival for patients with low versus high CD151 expression level was 94 vs. 41 months ( p =0.0451). CD151 expression in osteosarcoma cells with high metastatic potential was significantly higher than in those with low metastatic potential ( p

In this study, we evaluated the photodynamic efficacy of a new photosensitizer, benzochloroporphyrin derivative 18 (BCPD-18), in Ewing sarcoma. We found that BCPD-18 decreased the viability of TC-71 cells irradiated by 670 nm laser in a concentration dependent manner. We also observed cells undergoing apoptosis as well as cell cycle arrest at the G2M phase after BCPD–18-mediated photodynamic therapy (BCPD-PDT). In addition, in vivo study (subcutaneous and orthotopic models) showed that BCPD-PDT reduced tumor size, tumor weight and tumor-bearing leg weight. After PDT, apoptosis was shown in vivo. Bax expression was increased, and Bcl-2 expression was decreased. This study provides evidence that BCPD-18 could probably be a useful photosensitizer in PDT for Ewing sarcoma.

Osteosarcoma (OS) is ranked as the most common primary bone malignancy in children and adolescents worldwide, and the 5-year overall survival rate of OS is not optimistic. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been implicated in tumor cell growth, proliferation, and anti-apoptosis in OS. Therefore, the discovery of novel molecular compounds that can effectively block STAT3 activation, is essential for the treatment of OS and improving prognosis. Here, we investigate whether Glaucocalyxin A (GLA), derived from Rabdosia japonica, exhibit the potential anticancer effects in OS. First of all, we identify that GLA potently suppressed cell proliferation, induced G2/M phase arrest and promoted substantial apoptosis in OS. Next, we conclude that GLA could induce Reactive oxygen species (ROS)-mediated oxidative stress via an imbalance of GSH and GSSG. Then, we elucidate for the first time that GLA could significantly inhibit both constitutive and IL-6-inducible activation of STAT3 (Tyr705) and JAK2, the upstream regulator of STAT3. Furthermore, we elucidate that the inhibition of STAT3 is mainly induced by ROS-mediated oxidative stress. Overall, our findings demonstrate that GLA could exhibit potent anticancer effects through effectively blocking the STAT3 signaling pathway, which was induced by ROS-mediated oxidative stress in OS in vitro and in vivo.

The gelsolin (GSN) has been involved in the regulation of tumor formation and development, but the biological role of GSN in the pathogenesis of osteosarcoma (OS) has not been well characterized. In this study, we show that high expression of GSN was observed in OS tissues and correlated with tumor size, advanced Enneking stage, and poor patient prognosis. Knockdown of GSN significantly inhibited cell proliferation and invasiveness in the OS cell lines. Furthermore, stable overexpression of GSN in OS cells resulted in a significant increase in cell growth and motility with the downregulation of p-AKT and p-P38 pathway. Finally, overexpression of GSN promoted growth of OS tumors in SCID mice. Taken together, these results provided the first evidence that GSN might contribute to OS cancer development and could be an attractive therapeutic target for patients with OS.

Objective To reveal the alterations in quality of life (QOL) in bone metastases patients after magnetic resonance guided focused ultrasound (MRgFUS). Methods This retrospective study enrolled 26 patients diagnosed with bone metastases. Patients had various primary malignant tumors and tumor lesions in different locations. All patients received MRgFUS for bone metastasis. Each focal spot sonication pulse that was applied to create energy deposition lasted 20 s and was performed at a frequency of 1.05 MHz. The visual analog scale (VAS) was used to measure pain level and the EORTC QLQ-BM22 was applied to evaluate QOL for 12 months. The lower the QLQ-BM22 score, the better the QOL of patients. Results The painful site subscale of the EORTC QLQ-BM22 was observed without significant change. Significant reductions in the functional subscales were observed after therapy compared with the baseline. The functional interference was reduced significantly during the first 12 months. From the 2-month time point onwards, the pain characteristics subscale also decreased significantly. VAS scores had decreased by 40.8% 1 month after the operation and had decreased 10.9% compared with VAS scores preoperation. Scores for pain characteristics decreased by 28.8% after the operation and the scores were still down by 10.8% 1 year after the treatment. VAS scores indicated a significant reduction in pain over the course of the research until the 12-month time point follow-up compared with the baseline. Conclusion MRgFUS therapy improved the QOL of patients with bone metastasis by relieving bone pain.

Two-color stimulated Raman scattering (SRS) microscopy with label-free mapping of lipid/protein distributions has shown promise in virtual histology. Despite previous demonstrations of SRS in tumor delineation and diagnosis, the speed and efficiency of the current technique requires further improvements for practical use. Here, we integrate parallel dual-phase SRS detection with strip mosaicing, which reduces the imaging time of a whole mouse brain section from 70 to 8 minutes. We further verified our method in imaging fresh human surgical tissues, showing its great potential for rapid SRS histology, especially for large scale, large quantity imaging tasks.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo-resistance of OS, and could be used as potential therapeutic targets in OS.

Combretastatin A-4 (CA-4), a tubulin-depolymerizing agent, shows promising antitumor efficacy and has been under several clinical trials in solid tumors for 10 years. Autophagy has an important pro-survival role in cancer therapy, thus targeting autophagy may improve the efficacy of antitumor agents. N-myc downstream-regulated gene 1 (NDRG1) is a significant stress regulatory gene, which mediates cell survival and chemoresistance. Here we reported that CA-4 could induce cell-protective autophagy, and combination treatment of CA-4 and autophagy inhibitor chloroquine (CQ) exerted synergistic cytotoxic effect on human osteosarcoma (OS) cells. Meanwhile, CA-4 or CQ could increase the expression of NDRG1 independently. We further performed mechanistic study to explore how CA-4 and CQ regulate the expression of NDRG1. Using luciferase reporter assay, we found that CA-4 transcriptionally upregulated NDRG1 expression, whereas CQ triggered colocalization of NDRG1 and lysosome, which subsequently prevented lysosome-dependent degradation of NDRG1. Further, we showed that knockdown of NDRG1 caused the defect of lysosomal function, which accumulated LC3-positive autophagosomes by decreasing their fusion with lysosomes. Moreover, NDRG1 inhibition increased apoptosis in response to combination treatment with CA-4 and CQ. Taken together, our study revealed abrogation of NDRG1 expression sensitizes OS cells to CA-4 by suppression of autophagosome–lysosome fusion. These results provide clues for developing more effective cancer therapeutic strategies by the concomitant treatment with CA-4 and clinical available autophagy inhibitors.

Sarcomas are the neoplasms which arise in bone and peri-osseous soft tissues. Osteosarcoma, Ewing’s sarcoma and Chondrosarcoma are the 3 major malignancies of bone sarcoma affecting both children and adults. Among those, osteosarcoma is the most common bone-originated cancer in young ages. Although the primary tumor is often surgically resected and the improvements in therapeutic strategies were achieved in recently years, the outcomes remain poor with 50-60% of 5-year survival rates because of relapses mainly due to the metastases, especially metastases to lung. Soft tissue sarcomas are mesenchymal neoplasms including different histologic subtypes which can arise from viscera such as genitourinary, gastrointestinal or gynecologic organs, or from nonviscera soft tissues such as muscle, adipose, synovium etc. Among various subtypes of soft tissue sarcoma, synovial sarcoma is an aggressive malignancy that accounts for 10%-20% of soft tissue sarcoma in young population. Surgical excision combined with adjuvant or neoadjuvant radiotherapy provides a good treatment of local disease, but the recurrences often occurs with the most common pattern of metastasis to lung. Despite the increasing risk of sarcoma and poor outcome, effective treatments, especially precision therapies, are largely lacking. Breakthrough drug discovery is hindered by limited numbers of suitable in vivo models. In recent decades, patient-derived xenograft (PDX) mouse models are commonly used for drug efficacy evaluation with prominent advantages of similar histopathology and molecular pathology with patient tumors. We have established a series of patient derived xenograft models, recapitulating diverse subtypes of sarcoma, including bone sarcoma and soft tissue sarcoma. More than 30 osteosarcoma PDX models are established with a wide spectrum of age populations and clinical grades. Half of these osteosarcoma PDX models are derived from children and young adults. 2 of these osteosarcoma PDX models are derived from relapse tumors and 5 of them are from metastatic tumors (mainly from lung metastases). Besides, we have also established one Ewing’s sarcoma (derived from a 9-years-old child) and 5 Chondrosarcoma PDX models. We have also collected numbers of soft tissue sarcoma samples, of which, we have established 9 synovial sarcoma PDX models, mostly derived from adult patients with 2 of them derived from lung metastatic tumors. Among these PDX models derived from metastasis tumors, we also have established several matched PDX models with their primary tumors. Taken together, our established sarcoma PDX models include different subtypes and different cancer stages (especially primary vs. metastatic tumors), providing a valuable preclinical platform for the understanding of different pathogenesis, as well as supporting drug discovery efforts on different subtypes of sarcomas. Citation Format: Jessie Jingjing Wang, Mengxiong Sun, Likun Zhang, Yingqi Hua, Henry Qixiang Li, Davy Xuesong Ouyang. Establishment of sarcoma PDX models with various subtypes for drug efficacy evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4609.

Adalimumab is a fully human, anti-TNF monoclonal antibody of proven efficacy and safety in the treatment of the signs, symptoms and functional disability of ankylosing spondylitis (AS). A systematic review and meta-analysis was performed to assess the efficacy and safety of adalimumab treatment, relative to a placebo, in adult patients with AS. In the efficacy meta-analysis, significantly more patients in the adalimumab group achieved Assessment in AS International Working Group (ASAS)20 and Bath AS Disease Activity Index (BASDAI)50 compared with patients in the placebo group. Patients in the adalimumab group also showed significant improvement in BASDAI and health-related quality of life. With regard to adverse events, any adverse events and injection-site reaction were significantly higher in the adalimumab group compared with the control group. This meta-analysis shows a higher efficacy of adalimumab relative to placebo, but clinicians should be careful regarding adverse events in adalimumab-treated patients.

BACKGROUND Thoracolumbar vertebral metastasis (TVM) affects a large number of cancer patients. However, safe and effective palliative care remains controversial. The aim of the present study was to investigate the safety and efficacy of minimally invasive image-guided radiofrequency ablation (RFA) with percutaneous kyphoplasty (PKP) for TVM treatment. MATERIAL AND METHODS A retrospective study of 26 patients (mean age: 59.31 ± 11.62 years) was conducted, including 38 vertebral metastases at T11, T12, L1, L2, L3, L4, L5, and S1 with abundant blood vessels. Patients underwent RFA with PKP (4-6 min, 95 ± 5°C, 150 W, effective electrode area of 1.5-2.0 cm) under general anesthesia from February 2005 to January 2009. Electrodes were inserted into the lesions and pre- and post-operative visual analog scale (VAS) scores and X-rays were collected on day 3, week 1, and months 1, 3, and 6. Tumor recurrence and pain level were also evaluated. Safety assessment was conducted based on complications and adverse events. The mean follow-up time was 8.4 ± 2.1 months. RESULTS A mean of 2.69 ± 0.93 ablation was performed per patient. The ablation procedure required a mean of 15.08 ± 4.64 min, while the injection of bone cement required a mean of 6.73 ± 0.83 min, for a mean total operating time of 47.77 ± 7.13 min. Postoperative VAS scores were significantly lower on day 3, week 1, and months 1, 3, and 6 (P

Background context Surgical treatment of sacral giant cell tumors (GCTs) is associated with a high rate of complications, and there is controversy over which type of surgical treatment is optimal. Purpose To develop an optimal treatment strategy for sacral GCTs. Study design/setting Retrospective/academic medical center. Patient sample A total of 32 patients (18 women and 14 men) with sacral GCT who underwent surgery between August 1996 and August 2008. Outcome measures Local recurrence rate, surgical margins, blood loss, sacral nerve root preservation, and complications. Methods The medical charts of 32 patients were reviewed. Results Patients underwent either wide resection (n=2), marginal resection (n=11), marginal resection plus curettage (n=12), or curettage alone (n=7). The curettage group and the wide resection group had the highest and lowest amounts of blood loss (4,500 vs. 1,300 mL, respectively). During follow-up (median, 42 months), 12 patients (37.5%) had local recurrence, including five of seven in the curettage group. The recurrence rate was significantly lower in the marginal excision group compared with that in the curettage group (18.2% vs. 71.4%, respectively; p=.049). Five patients had bladder dysfunction, and two patients had bowel dysfunction. Four patients who underwent marginal resection had lower limb dysfunction. Overall survival was 93.6%, and 2-year recurrence-free survival was 84.4%. Conclusions Choosing an optimal surgical margin in the treatment of sacral GCTs is of great importance for local recurrence control and sacral nerve root preservation. Curettage alone should not be used to treat sacral GCT.

Background/Aims: Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer. However, the molecular mechanisms of down-regulation Hsp90 expression in osteosarcoma are incompletely understood. To develop potential therapy targeting Heat shock protein 90B1 (Hsp90B1), we studied the roles of miR- 223 in the proliferation and apoptosis of human osteosarcoma. Methods: pcDNA3.1(+)- miR-223 plasmid vectors were constructed and transfected into MG63 cells. Co-transfection of miR-223 expression vector with pMIR-Hsp90B1 (The recombined vector of pMIR-GLOTM luciferase vector containing Hsp90B1-3′UTR) led to the reduced activity of luciferase in a dual-luciferase reporter gene assay, suggesting that Hsp90B1 is a target gene of miR-223. Expression of HSP90B1 was detected by RT-PCR and western blotting analysis. Cell proliferation was determined using the MTT assay. Cell-cycle distribution and apoptosis were examined by flow cytometry. PI3K, p-Akt, Akt, mTOR, Bcl-2 and Bid were also detected by western blotting analysis. After a mouse xenograft model of human MG63 tumors was constructed, tumor growth, microvessel density and proliferation in each group was determined. Results: The pcDNA3.1(+)-miR-223 vector efficiently suppressed the expression of HSP90B1, while silencing miR-223 increased expression of Hsp90B1. Furthermore, overexpression of miR-223 results in significant inhibition of cell growth on culture plates. Moreover, cancer cells showed significant G0/G1 arrest and increased apoptosis due to gene silencing. Protein levels of PI3k, p-Akt, mTOR, and Bcl-2 were decreased, whereas Bid levels were increased. Microvessel density as assessed by CD34 levels and cell growth by PCNA levels decreased according to immunohistochemical analysis. Conclusion: Hsp90B1 is a direct target of miR-223 and miR- 223 may have a tumor suppressor function in osteosarcoma through the PI3K/Akt/mTOR pathway and could be used in anticancer therapies in osteosarcoma.

This study was undertaken to investigate the inhibitory effects of triterpenoid compound oleanolic acid and its synthetic derivatives on osteosarcoma cells in order to identify new therapeutic candidates for the treatment of this disease. We used the 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl tetrazolium bromide assay to assess the effect of oleanolic acid compounds on the proliferation of osteosarcoma cells. The effect of dextrose-oleanolic acid (the most potent oleanolic acid derivative) on apoptosis of osteosarcoma cells was evaluated using the Annexin-V method. The cell cycle of dextrose-oleanolic acid-treated cells was examined by flow cytometry, and the in vivo effects of dextrose-oleanolic acid were evaluated in a mouse osteosarcoma model. Oleanolic acid compounds had an overall inhibitory effect on the proliferation of osteosarcoma cells. Our in vitro data showed that the dextrose-oleanolic acid derivative brought about maximal inhibition of proliferation of osteosarcoma cells while inducing apoptosis. It could also inhibit the growth of osteosarcoma and decreased the rate of lung metastasis in vivo. Of the oleanolic acid derivatives, dextrose-oleanolic acid exhibited the most potent anti-osteosarcoma activity; it may represent a new frontier in the treatment of osteosarcoma.

Correction to: Cell Death and Disease (2017) 8 (9):e3048. doi: 10.1038/cddis.2017.438; published online 14 September 2017 Since the publication of this paper, the authors have noted that there was an error in Figure 1d, in that, the GAPDH for combination treatment with CA-4 and CQ in SJSA cells by mistake duplicated for CQ alone treatment (Figure 3e).

This study was carried out to investigate the anti-tumor effect and mechanism of hiporfin-mediated photodynamic therapy (hiporfin-PDT) in osteosarcoma. We found that hiporfin accumulated mainly in the cytoplasm of osteosarcoma cells in a time and concentration-dependent manner. Hiporfin-PDT inhibited the proliferation, induced apoptosis and produced cell cycle arrest at G2M in osteosarcoma cell lines. Hiporfin-PDT increased the expression of cleaved-caspase-3, cleaved PARP-1, Bax and RIP1 while it decreased the expression of Bcl-2; in addition, low concentration of hiporfin increased LC3 conversion. Furthermore, cell death caused by hiporfin-PDT could be rescued by Nec-1 but not by Z-VAD-FMK. Production of reactive oxygen species was increased after hiporfin-PDT. In vivo studies showed a significant decrease in tumor volume and weight after hiporfin-PDT in all three tumor mouse models investigated (subcutaneous and orthotopic). Histological analysis showed widespread cell apoptosis and necrosis after treatment. Immunohistochemistry also showed upregulation of cleaved-caspase-3 and downregulation of Bcl-2 after hiporfin-PDT. These results indicate that hiporfin-PDT exhibits a killing effect in osteosarcoma both in vitro and in vivo, which is associated with apoptosis and necroptosis, while autophagy plays a protective role. All these findings shed light on a potential future clinical use for hiporfin in the treatment of osteosarcoma.

We investigated the antitumor effect and mechanism of hematoporphyrin monomethyl ether-mediated photodynamic therapy (HMME-PDT) in sarcomas. Intracellular uptake of HMME by osteosarcoma cells (LM8 and K7) was time- and dose-dependent, while this was not observed for myoblast cells (C2C12) and fibroblast cells (NIH/3T3). HMME-PDT markedly inhibited the proliferation of sarcoma cell lines (LM8, MG63, Saos-2, SW1353, TC71, and RD) (P

Background Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and adolescents. However, the knowledge in diagnostic modalities has progressed less. To identify new biomarkers for the early diagnosis of OS as well as for potential novel therapeutic candidates, we performed a sub-cellular comparative proteomic research. Methods An osteosarcoma cell line (MG-63) and human osteoblastic cells (hFOB1.19) were used as our comparative model. Plasma membrane (PM) was obtained by aqueous two-phase partition. Proteins were analyzed through iTRAQ-based quantitative differential LC/MS/MS. The location and function of differential proteins were analyzed through GO database. Protein-protein interaction was examined through String software. One of differentially expressed proteins was verified by immunohistochemistry. Results 342 non-redundant proteins were identified, 68 of which were differentially expressed with 1.5-fold difference, with 25 up-regulated and 43 down-regulated. Among those differential proteins, 69% ware plasma membrane, which are related to the biological processes of binding, cell structure, signal transduction, cell adhesion, etc., and interaction with each other. One protein--CD151 located in net nodes was verified to be over-expressed in osteosarcoma tissue by immunohistochemistry. Conclusion It is the first time to use plasma membrane proteomics for studying the OS membrane proteins according to our knowledge. We generated preliminary but comprehensive data about membrane protein of osteosarcoma. Among these, CD151 was further validated in patient samples, and this small molecule membrane might be a new target for OS research. The plasma membrane proteins identified in this study may provide new insight into osteosarcoma biology and potential diagnostic and therapeutic biomarkers.

The objective of this study was to evaluate the efficacy and safety of fibrin sealant in patients following total knee arthroplasty (TKA). A comprehensive literature search of the electronic databases PubMed, MEDLINE, Web of Science, and Cochrane Library for published randomized controlled trials (RCTs) was undertaken. The evidence base was critically appraised using a tool from the Cochrane Bone, Joint and Muscle Trauma Group. Eight RCTs involving 641 patients were included. The use of fibrin sealant significantly reduced postoperative drainage (weighted mean difference (WMD) −346, 95% confidence interval (CI) −496.29 to −197.54, P