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Purpose Glucocorticoid-induced osteonecrosis of the femoral head (GC-induced ONFH) is a rebarbative disease affecting people from all ages, especially young adults, and often leads to severe joint pain and limitations on physical activity. Numerous studies have reported that ABCB1 polymorphisms are associated with GC-induced ONFH, but the results are inconclusive, partially because the sample size of published studies is relatively small. Therefore, we performed a meta-analysis including seven case–control studies to estimate such association. Methods Published literature from Medline, Embase, and CNKI were searched for eligible publications. Pooled odds ratio (OR) together with their 95% confidence (CI) was calculated using a fixed effect model or random effect model. The meta-analysis was performed in accordance to PRISMA Statement Criteria. Results The ABCB1 3435T allele reduces the GC-induced ONFH risk based on the evidence from the co-dominant model (CT vs. CC, OR = 0.73, 95% CI: 0.53–1.00; TT vs. CC, OR = 0.43, 95% CI: 0.26–0.69), dominant model (CT+TT vs. CC, OR = 0.64, 95% CI: 0.48–0.87), allele contract model, (T vs. C, OR = 0.68, 95% CI: 0.54–0.84), and recessive model (TT vs. CC+CT, OR = 0.52, 95% CI: 0.34–0.81). Similarly, the ABCB1 2677T/A allele reduce the GC-induced ONFH risk based on the evidence from the co-dominant model (GT/A vs. GG, OR = 0.66, 95% CI: 0.45–0.96; T/AT/A vs. GG, OR = 0.52, 95% CI: 0.34–0.82), dominant model (GT/A+T/AT/A vs. GG, OR = 0.61, 95% CI: 0.43–0.87), and allele contract model (T/A vs. G, OR = 0.73, 95% CI: 0.58–0.90). Conclusions The meta-analysis revealed that 3435T allele and ABCB1 2677T/A allele may decrease the risks of GC-induced ONFH. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neuroblastoma (NBL) is a common pediatric solid tumor, and outcomes for patients with advanced neuroblastoma remain poor despite extremely aggressive treatment. Chemotherapy resistance at relapse contributes heavily to treatment failure. The poor survival of patients with high-risk NBL prompted this investigation into novel treatment options with the objective of gaining a better understanding of resistance mechanisms. On the basis of previous work and on data from publicly available studies, the authors hypothesized that human epidermal growth factor receptor 4 (Her4) contributes to resistance. METHODS: Her4 expression was reduced with small-hairpin RNA (shRNA) to over express intracellular HER4, and the authors tested its impact on tumor cell survival under various culture conditions. The resulting changes in gene expression after HER4 knockdown were measured by using a messenger RNA (mRNA) array. RESULTS: HER4 expression was up-regulated in tumor spheres compared with the expression in monolayer culture. With HER4 knockdown, NBL cells became less resistant to anoikis and serum starvation. Moreover, HER4 knockdown increased the chemosensitivity of NBL cells to cisplatin, doxorubicin, etoposide, and activated ifosfamide. In mRNA array analysis, HER4 knockdown predominately altered genes related to cell cycle regulation. In NBL spheres compared with monolayers, cell proliferation was decreased, and cyclin D expression was reduced. HER4 knockdown reversed cyclin D suppression. Overexpressed intracellular HER4 slowed the cell cycle and induced chemoresistance. CONCLUSIONS: The current results indicated that HER4 protects NBL cells from multiple exogenous apoptotic stimuli, including anoikis, nutrient deficiency, and cytotoxic chemotherapy. The intracellular fragment of HER4 was sufficient to confer this phenotype. HER4 functions as a cell cycle suppressor, maintaining resistance to cellular stress. The current findings indicate that HER4 overexpression may be associated with refractory disease, and HER4 may be an important therapeutic target. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Tumor angiogenesis, immunosuppression, and progression are all closely correlated with the tumor microenvironment (TME). Immune evasion is supported by both M2 phenotype tumor-associated macrophages (TAMs) and vascular aberrations in the TME. TME reprogramming is a promising therapeutic approach for treating tumors. Anti-angiogenesis has the power to control the polarization of macrophages, prevent progression, and increase drug penetration. Additionally, polyamine blocking therapy can increase CD8+ T cell infiltration and decrease immunosuppressive cells. These results led to developing a potential therapeutic regimen that targets TAMs and angiogenesis to reprogram the osteosarcoma TME. Results: For the targeted biomimetic co-delivery of regorafenib and alpha-difluoromethylornithine via the mannose receptor, which is overexpressed in both TAMs and osteosarcoma cells, mannosylated poly(lactide-co-glycolide)-polyethylene glycol nanoparticles (Man-NPs) were synthesized. The superior physiological properties and intratumoral accumulation of the Man-NPs efficiently promoted TAMs polarization and inhibited angiogenesis. Macrophage repolarization further activated immune cells, which contributed to remodeling the TME. Conclusion: Overall, these findings suggested that using Man-NPs as an immunotherapeutic approach to treat osteosarcoma may be promising. [ABSTRACT FROM AUTHOR]

Immunotherapy has gradually become an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Cytokine therapy is a promising treatment for cancer immunotherapy. Currently, there are many preclinical theoretical bases to support this treatment strategy and a variety of cytokines in clinical trials. When cytokines were applied to tumor immunotherapy, it was found that the efficacy was not satisfactory. As research on tumor immunity has deepened, the role of cytokines in the tumor microenvironment has been further explored. Meanwhile, the study of nanomaterials in drug delivery has been fully developed in the past 20 years. Researchers have begun to think about the possibility of combining cytokine therapy with nanomaterials. Herein, we briefly review various nano-delivery systems that can directly deliver cytokines or regulate the expression of cytokines in tumor cells for cancer immunotherapy. We further discussed the feasibility of the combination of various therapies. We looked forward to the main challenges, opportunities, and prospects of tumor immunotherapy with multiple cytokines and a nano-delivery system. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLC1. Functionally, sphingolipid synthesis and the SPTLC1 inhibitor, myriocin, significantly suppressed the clonogenic growth of CD151-overexpression cells. Importantly, myriocin selectively restrained CD151-high expression tumor growth in preclinical patient-derived xenograft models. Collectively, these data establish that CD151 is a key mediator of sphingolipid metabolism and provide a new approach to developing novel CD151-based targeted therapies for osteosarcoma. [ABSTRACT FROM AUTHOR]

Objective: To retrospectively analyze and compare the relationship between the success rate of patient‐derived xenograft (PDX) modeling of osteosarcoma and prognosis (3‐year overall survival rate and disease‐free survival rate) and incidence of lung metastasis. Methods: The sample group consisted of 57 osteosarcoma patients with definite pathological diagnoses from Shanghai General Hospital from 2015–2017. PDX models in 57 patients were analyzed by retrospective analyses. Among the patients currently inoculated, 20 were tumorigenic in the PDX model, and 37 were nontumorigenic. According to the tumorigenicity of PDXs, the corresponding osteosarcoma patients were divided into two groups. The effects of clinically related indicators on the model were retrospectively compared. The patients were followed, and the 3‐year survival, 3‐year disease‐free survival (DFS), and lung metastasis rates were collected. The relationship between the modeling success and patient prognosis was investigated. Results: In the chemotherapy‐treated group, the PDX modeling success rate was 17.4%, and in the nonchemotherapy group, the success rate was 47.1%. The success of PDX modeling was related to whether patients received chemotherapy. The success rate of PDX modeling is significantly reduced after receiving chemotherapy. The 3‐year overall survival rate of the PDX‐grafted group was 49.23%, and that of the PDX‐nongrafted group was 65.71%. There was a significant difference between the two groups, showing a strong negative correlation between the 3‐year survival rate and the success rate of the PDX model. The 3‐year disease‐free survival rate of the PDX‐grafted group was 29.54%. The 3‐year DFS of the PDX‐nongrafted group was 50.34%. There was a significant difference between the two groups. Lower grafted rates indicate a higher DFS rate. The incidence of lung metastasis in the PDX‐grafted group was 32.4%, and that in the nongrafted group was 13.1%. There was a significant difference between the two groups. The successful establishment of the PDX model indicates that patients are more likely to have lung metastases. Conclusions: The success of PDX modeling often indicates poor prognosis (low 3‐year overall survival rate and disease‐free survival rate) and a greater possibility of lung metastasis. Therefore, PDX modeling in osteosarcoma patients can accurately predict the prognosis of patients and the risk of lung metastasis in advance to help us develop better therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is the most common primary bone cancer in adolescents and lung metastasis is the leading cause of death in patients with OS. However, the molecular mechanisms that promote OS growth and metastasis remain unknown. Methods: We investigated the expression of myosin light chain kinase family members between metastasis and non-metastasis patients in the TARGET database and ensured that only myosin light chain kinase family member 4 (MYLK4) had higher expression in metastatic osteosarcoma patients. Then we confirmed the results by immunohistochemistry (IHC) and Western blotting (WB) of OS tissues. The effect of MYLK4 on the metastasis and proliferation of OS cells was investigated by wound healing, Transwell and colony-formation assays. Mass spectrum analysis was used to ensure the new binding protein of MYLK4. Tissue microarrays analysis was used to show the correlation between MYLK4 and pEGFR (Y1068). A series of in vivo experiments were conducted to reveal the mechanisms by which MYLK4 modulated the metastasis and proliferation of OS. Results: Myosin Light Chain Kinase Family Member 4 (MYLK4) was significantly upregulated in metastatic human OS tissues. Growth and metastasis of OS could be accelerated by MYLK4 overexpression, whereas silencing MYLK4 expression resulted in decreased cell growth and metastasis. Mechanistically, mass spectrum analysis showed that MYLK4 interacted with the epidermal growth factor receptor (EGFR) in osteosarcoma cells and promoted growth and metastasis via the EGFR signaling pathway. Tissue microarrays analysis also showed that MYLK4 expression had a positive correlation with the expression of pEGFR (Y1068). Moreover, the EGFR inhibitor gefitinib could partially reverse the effect of cell proliferation and metastasis caused by MYLK4 overexpression. Importantly, the combination of MYLK4 and EGFR inhibitors had synergistic effects on growth and metastasis of OS in vitro and in vivo. Conclusion: Our results indicate that MYLK4 promotes OS growth and metastasis by activating the EGFR signaling pathway and can be a novel therapeutic target for the treatment of OS patients. [ABSTRACT FROM AUTHOR]

Objective: Whether H3.3 K36M mutation (H3K36M) could be an approach if the diagnosis of chondroblastoma (CB) patients was indistinct and it was suspected to be unclear clinically. Methods: We reviewed and compared our clinical experiences of CB cases and some suspected cases, which were not diagnosed distinctly, between 2013 to 2019. A total of 15 male and four female cases included in this study were seperated into two groups, CB group and suspected case (SC) group. The CB group included 13 men and 3 women, with an age range from 9 to 54 (mean age, 22 years old). The SC group included two men and one woman, with the age range from 13 to 25 (mean age, 19 years old). In both groups the patients had been followed‐up until December 2019 and none of the patients had prior treatment history. We evaluated the clinical complaints, radiological features, and clinical‐histological features of the cases and performed an immunohistochemical (IHC) study to detect whether the H3K36M expression of cases was different, consistent with a gene‐mutation analysis. Results: In both groups, the radiologic features of both groups appeared as round low‐density shadow with a clear edge, pathologic features showed diffuse proliferation of neoplastic cells with multinuclear giant cells. The radiological tumor size of CB group and SC group showed little difference, which was about 29.0*21.6 mm. Clinical‐immunohistochemical features of both groups showed chondroid matrix inside with naïve tumor cells, multinucleated giant cells, and ground substance cells. Most of them showed chondro‐related antibody positive (12 cases) but some of them showed S‐100 negative (four cases). The clear difference of both groups was the result of H3K36M IHC study and gene analysis. In our cases, the CB group showed diffuse H3K36M positive and the SC group showed negative. The gene mutation analysis revealed that H3K36M‐positive CB patients had K36M mutation, which were not found in the SC group. Sanger sequencing showed an A > T substitution at codon 36 of histone H3F3B. No other types of histone H3 mutation was detected in the CB group. Particularly, one of the suspected cases showed a G34W mutation was confirmed to be a giant cell tumor of bone (GCTB). Conclusions: Our study showed H3K36M immunohistochemistry and gene mutation analysis were specific clinical diagnostic tools to distinguish suspected CB from other giant cell‐rich or cartilage matrix‐diffuse bone tumors. The clinical‐radiological and histomorphological features of patients gave suggestions on whether the H3K36M IHC and gene analysis should be required. [ABSTRACT FROM AUTHOR]

Despite the growing recognition of metabolic reprogramming as an important hallmark of cancer in the past few years, the molecular mechanisms underlying metabolic alterations during tumorigenesis remain unclear. In this study, we identified a critical role of Her4 in rewiring cancer metabolism toward tumor-promoting metabolic processes, including increased glycolysis, glutaminolysis, mitochondrial biogenesis, and oxidative phosphorylation, which may in part cooperate to promote tumorigenesis. We found that overexpression of Her4 promoted the stabilization of c-Myc through a CIP2A-mediated increase in c-MycS62 phosphorylation and GSK3β-mediated decrease in c-MycT58 phosphorylation, both of which decreased c-Myc degradation. Furthermore, Her4 was found to increase glucose uptake and tumor growth in an osteosarcoma xenograft model. Overall, these findings provide a better understanding of the involvement of Her4 in tumorigenesis and document its potential role in metabolic reprogramming for the first time. We believe that our study might lead to promising opportunities for targeted metabolic therapy for cancer. [ABSTRACT FROM AUTHOR]

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. Unlabelled Image • Glaucocalyxin A effectively blocks STAT3 signaling pathway through ROS-mediated oxidative stress due to an imbalance of GSSG/GSH in osteosarcoma cells. • Glaucocalyxin A induces GR activity via downregulating the mRNA and protein level of GR in vitro. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

During tumorigenesis and development, participation of the tumor microenvironment is not negligible. As an important component in the tumor microenvironment, mesenchymal stem cells (MSCs) have been corroborated to mediate proliferation, metastasis, and drug resistance in many cancers, including osteosarcoma. What's more, because of tumor site tropism, MSCs can be engineered to be loaded with therapeutic agents so that drugs can be precisely delivered to tumor lesions. In this review, we mainly discuss recent advances concerning the functions of MSCs in osteosarcoma and their possible clinical applications in the future. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) has traditionally been defined as a non-inflammatory disease. Recently, many studies have demonstrated that OA also has an inflammatory component. BRD4, a member of the Bromodomain and Extra-Terminal Domain family, has emerged as an important regulator of some chronic inflammatory diseases. JQ1, an antagonist of BRD4, modulates transcription of several genes. Our study demonstrated that BRD4 is up-regulated in articular cartilage of OA. BRD4 inhibition attenuated the inflammation and catabolism of chondrocytes and suppressed NF-κB signalling pathway activation. In addition, BRD4 inhibition abolished the transcriptional activity of High Mobility Group Protein B1 (HMGB1). We identified HMGB1 as a direct target of BRD4. Genetic and pharmacological inhibition of BRD4 suppressed IL-1β-induced expression and translocation of HMGB1. Chromatin immunoprecipitation (ChIP) showed the enrichment of BRD4 around the HMGB1 upstream non-promoter region, which diminished with JQ1 treatment. Finally, haematoxylin & eosin and Safranin o/Fast Green staining demonstrated that JQ1 attenuates cartilage destruction in mice with anterior cruciate ligament transection without significant toxic effects. These studies highlighted the importance of BRD4 in the chronic inflammatory reactions of OA, which, as far as we know, was the first report of this finding, and suggested that BRD4 might be a novel potential therapeutic target for the treatment of OA. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common primary bone malignancy in children and adolescents; it exhibits rapid growth and a high metastatic potential and may thus lead to relatively high mortality. The JAK2/STAT3 signaling pathway, which plays a critical role in the occurrence and development of osteosarcoma, is a potential target for the treatment of osteosarcoma. Here, we identified the natural product telocinobufagin (TCB), which is a component isolated from toad cake, as a potent candidate with anti-osteosarcoma effects. TCB inhibited osteosarcoma cell growth, migration, invasion and induced cancer cell apoptosis. Mechanistically, TCB specifically inhibited the JAK2/STAT3 signaling pathway. More importantly, TCB significantly suppressed tumor growth and metastasis in an osteosarcoma xenograft animal model. Moreover, TCB also showed strong inhibitory effects in other cancer types, such as lung cancer, liver cancer, colon cancer, breast cancer and gastric cancer. Hence, our study reveals TCB as a potent anti-osteosarcoma therapeutic agent that inhibits the JAK2/STAT3 signaling pathway. [Display omitted] • TCB suppresses the proliferation, migration and invasion of osteosarcoma cells. • TCB inhibits the growth and metastatsis of osteosarcoma via inhibiting JAK2/STAT3 signaling pathway. • TCB suppresses cell proliferation and invasion in other types of tumors. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25–30 years. Arsenic sulfide (As 2 S 2 ), 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 As 2 S 2 in osteosarcoma both in vitro and in vivo . In this study, we demonstrated that As 2 S 2 potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with As 2 S 2 induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, −8, −9. As 2 S 2 was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that As 2 S 2 -induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that As 2 S 2 inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase As 2 S 2 -induced apoptosis and autophagy. Finally, As 2 S 2 in vivo suppressed tumor growth with few side effects. In summary, our results revealed that As 2 S 2 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. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity. [Display omitted] • STAT3 pathway may represent a promising target for therapeutic intervention in osteosarcoma. • pectolinarigenin is a potent inhibitor of STAT3 signaling in osteosarcoma. • Pectolinarigenin inhibits osteosarcoma tumor growth and metastasis in vivo. • pectolinarigenin shows few side effects on mouse. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare and evaluate the event of VTE (Venous Thromboembolism Event) after total artificial joint replacement between two groups diagnosed with either musculoskeletal tumors or osteoarthritis (OA) of the knee. From 2004 to 2014, a total of 1,402 patients (308 in tumor group, 1,094 in OA group) were involved in this study. The rate of asymptomatic DVT (Deep vein thrombosis) was significantly higher in tumor group when compared with OA group. Though both the incidence of symptomatic DVT and PE (Pulmonary embolism) were slightly higher in tumor group, no significant difference was detected. Tumor patients suffered an almost equal risk of VTE compared with OA patients except a higher rate of asymptomatic DVT after total artificial joint replacement. For patients with tumor, no significant association was observed between any potential risk factor and DVT. [ABSTRACT FROM AUTHOR]

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 G2 M 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. [ABSTRACT FROM AUTHOR]

ErbB receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ErbB inhibitors are now used in the clinical setting. A large number of studies have been conducted to examine the expression of ErbB family members in bone and soft tissue sarcomas, including osteosarcomas, synovial sarcomas, Ewing sarcomas, rhabdomyosarcomas, and so on. Nevertheless, the clinical implications of ErbB receptors remain elusive. To illustrate the potential of ErbB family members as prognostic and therapeutic drug targets in bone and soft tissue sarcomas, we summarized the molecular evidence and observations from clinical and basic trials. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and is characterized by frequent metastasis and resistance to chemotherapy. Because osteosarcoma cells are not highly susceptible to current chemotherapy drugs, new alternative strategies for the treatment of osteosarcoma are needed. This study was undertaken to investigate the inhibitory effects of a new synthetic ursolic acid derivative IUA on osteosarcoma cells and to explore its molecular mechanism. We also intended to identify new therapeutic candidates. Methods: We used MTT assay to assess the effect of IUA on the proliferation of osteosarcoma cells. Western-blot analysis was performed to examine downstream molecular events. The Annexin V method was used to evaluate the effect of IUA on apoptosis of osteosarcoma cells. The cell cycle of IUA-treated cells was examined by flow cytometry, and the in vivo effects of this new ursolic acid derivative were evaluated in a mouse osteosarcoma model. Results: The results showed that the new synthetic ursolic acid derivative IUA significantly decreased viability of osteosarcoma cells in vitro and in vivo. It could also induce apoptosis and G1 phase arrest of osteosarcoma cells. The JNK signaling pathway was significantly inhibited, and cleaved caspase-3 protein was increased. Conclusion: We concluded that the new synthetic ursolic acid derivative IUA induces proliferation inhibition and apoptosis of osteosarcoma cells in vitro and in vivo via the down-regulation of the JNK signaling pathway, making it a promising agent for the prevention and treatment of human osteosarcoma. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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<0.05), and the killing effect was improved with increased HMME concentration and energy intensity. Flow cytometry analysis revealed that LM8, MG63, and Saos-2 cells underwent apoptosis after treatment with HMME-PDT. Additionally, apoptosis was induced after HMME-PDT in a three-dimensional culture of osteosarcoma cells. Hoechst 33342 staining confirmed apoptosis. Cell death caused by PDT was rescued by an irreversible inhibitor (Z-VAD-FMK) of caspase. However, cell viability was not markedly decreased compared with the HMME-PDT group. Expression levels of caspase-1, caspase-3, caspase-6, caspase-9, and poly (ADP-ribose) polymerase (PARP) proteins were markedly up-regulated in the treatment groups and increased with HMME concentration as determined by western blot analysis. In vivo, tumor volume markedly decreased at 7–16 days post-PDT. Hematoxylin and eosin staining revealed widespread necrotic and infiltrative inflammatory cells in the HMME-PDT group. Immunohistochemistry analysis also showed that caspase-1, caspase-3, caspase-6, caspase-9, and PARP proteins were significantly increased in the HMME-PDT group. These results indicate that HMME-PDT has a potent killing effect on osteosarcoma cells in vitro and significantly inhibits tumor growth in vivo, which is associated with the caspase-dependent pathway. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma is the most frequent primary malignant bone tumor, notorious for its lung metastasis. Shikonin, an effective constituent extracted from Chinese medicinal herb, was demonstrated to induce necroptosis in some cancers.Methods: MTT assay was performed to detect cell survival rate in vitro. Flow cytometry was used to analyze cell cycle and cell death. Western blot was performed to determine the expression levels of RIP1, RIP3, caspase-3, caspase-6 and PARP. The tibial primary and lung metastatic osteosarcoma models were used to evaluate the anti-tumor effect of shikonin in vivo.Results: The cell survival rate was decreased in a dose and time dependent manner when treated with shikonin. No major change in cell cycle was observed after shikonin treatment. The cell death induced by shikonin could be mostly rescued by specific necroptosis inhibitor necrostatin-1, but not by general caspase inhibitor Z-VAD-FMK. The number of necrotic cells caused by shikonin was decreased after being pretreated with Nec-1 detected by flow cytometry in K7 cells. After 8-hour treatment of shikonin, the expression levels of RIP1 and RIP3 were increased while caspase-3, caspase-6 and PARP were not activated in K7 and U2OS cells determined by Western blot. Size of primary tumor and lung metastasis in shikonin treated group were significantly reduced. The protein levels of RIP1 and RIP3 in primary tumor tissues were increased by shikonin. The overall survival of lung metastatic models was longer compared with control group (p < 0.001).Conclusions: Shikonin had prompt but profound anti-tumor effect on both primary and metastatic osteosarcoma, probably by inducing RIP1 and RIP3 dependent necroptosis. Shikonin would be a potential anti-tumor agent on the treatment of primary and metastatic osteosarcoma. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NBL) is a common pediatric solid tumor, and outcomes for patients with advanced neuroblastoma remain poor despite extremely aggressive treatment. Chemotherapy resistance at relapse contributes heavily to treatment failure. The poor survival of patients with high-risk NBL prompted this investigation into novel treatment options with the objective of gaining a better understanding of resistance mechanisms. On the basis of previous work and on data from publicly available studies, the authors hypothesized that human epidermal growth factor receptor 4 (Her4) contributes to resistance.Methods: Her4 expression was reduced with small-hairpin RNA (shRNA) to over express intracellular HER4, and the authors tested its impact on tumor cell survival under various culture conditions. The resulting changes in gene expression after HER4 knockdown were measured by using a messenger RNA (mRNA) array.Results: HER4 expression was up-regulated in tumor spheres compared with the expression in monolayer culture. With HER4 knockdown, NBL cells became less resistant to anoikis and serum starvation. Moreover, HER4 knockdown increased the chemosensitivity of NBL cells to cisplatin, doxorubicin, etoposide, and activated ifosfamide. In mRNA array analysis, HER4 knockdown predominately altered genes related to cell cycle regulation. In NBL spheres compared with monolayers, cell proliferation was decreased, and cyclin D expression was reduced. HER4 knockdown reversed cyclin D suppression. Overexpressed intracellular HER4 slowed the cell cycle and induced chemoresistance.Conclusions: The current results indicated that HER4 protects NBL cells from multiple exogenous apoptotic stimuli, including anoikis, nutrient deficiency, and cytotoxic chemotherapy. The intracellular fragment of HER4 was sufficient to confer this phenotype. HER4 functions as a cell cycle suppressor, maintaining resistance to cellular stress. The current findings indicate that HER4 overexpression may be associated with refractory disease, and HER4 may be an important therapeutic target. [ABSTRACT FROM AUTHOR]

• Osteosarcoma (OS) could be divided into two subtypes based on immune-related gene sets. • High immune cell infiltration subtype of OS predicted better prognosis. • Significant differences in immune cell infiltration were shown between two OS subtypes. • Verifying a new immune-related gene prognostic signature based on differentially expressed genes between two OS subtypes. Osteosarcoma (OS) is a highly aggressive cancer with poor prognosis, which mainly occurs in teenagers. Recent studies have shown that tumor-infiltrating immune cells play an important role in the progression of OS. In the present study, we identified two immune subtypes of OS (referred to as high and low immune cell infiltration subtypes, respectively) based on immune-related gene sets using TARGET and GEO cohort datasets. Elevated immune scores, increased stromal scores, decreased tumor purities, and higher infiltration of CD8 + T cells and M1 macrophages were observed for the high immune cell infiltration subtype. Moreover, the high immune cell infiltration subtype was characterized by high expression of immune checkpoint molecules. Gene set enrichment analysis showed that "B cell receptor signaling pathway" and "T cell receptor signaling pathway" gene sets were enriched in the high immune cell infiltration subtype. In addition, patients in the high immune cell infiltration subtype had better prognosis than patients in the low immune cell infiltration subtype. Furthermore, differentially expressed genes were screened according to the two OS subtypes and a risk model was generated by multivariate Cox regression analysis to predict the prognosis of OS patients. These results in this study showed that OS patients could be divided into two immune subtypes and offered a novel two-gene risk signature to predict the prognosis of patients with OS. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to present and evaluate surgical resection and reconstructive techniques using autologous femoral head bone-grafting in treating partial acetabular defects arising from primary pelvic malignant tumors.Methods: From January 2009 until January 2015, a total of 20 primary pelvic malignancy cases involving the acetabulum were retrospectively investigated. Surgical resections and reconstructions were conducted based on the type of the tumor with custom osteotomy guides and autologous femoral head bone-grafting. In all cases, prosthesis survival period, complication occurrence, and clinical outcomes data were collected and analyzed.Results: Thirteen male and 7 female patients with an average age of 48 years old (range 23-69 years old) were followed for a median of 69 months (range 48-112 months). Of these cases, 17 included chondrosarcomas and 3 additional patients with a malignant giant cell tumor of bone (MBGCT) as proven by pathology. During follow-up, 3 cases of chondrosarcoma recurred (15%), of which two cases received hemi-pelvic amputation, 1 case of MBGCT relapsed and developed pulmonary metastases. Two cases of acetabular prosthesis with an impending dislocation received closed reduction followed by 6 weeks of hip abduction brace fixation. One case of prosthesis loosening was revised. In another case a deep infection occurred with debridement and prosthesis removal. Musculoskeletal Tumor Society 1993 (MSTS-93) score was utilized to conduct functional evaluation: 13 cases were good, 6 were average and one was poor.Conclusion: The precision of the osteotomies performed is likely crucial for this type of reconstructive strategy to be successful. The use of custom guides for acetabular osteotomies and femoral head reconstruction can improve functional outcomes with relatively low complications at the intermediate length of follow-up. [ABSTRACT FROM AUTHOR]

Fullerene C60 nanocrystals (nano‐C60) possess various attractive bioactivities, including autophagy induction and calcium/calmodulin‐dependent protein kinase IIα (CaMKIIα) activation. CaMKIIα is a multifunctional protein kinase involved in many cellular processes including tumor progression; however, the biological effects of CaMKIIα activity modulated by nano‐C60 in tumors have not been reported, and the relationship between CaMKIIα activity and autophagic degradation remains unclear. Herein, nano‐C60 is demonstrated to elicit reactive oxygen species (ROS)‐dependent cytotoxicity and persistent activation of CaMKIIα in osteosarcoma (OS) cells. CaMKIIα activation, in turn, produces a protective effect against cytotoxicity from nano‐C60 itself. Inhibition of CaMKIIα activity by either the chemical inhibitor KN‐93 or CaMKIIα knockdown dramatically promotes the anti‐OS effect of nano‐C60. Moreover, inhibition of CaMKIIα activity causes lysosomal alkalinization and enlargement, and impairs the degradation function of lysosomes, leading to autophagosome accumulation. Importantly, excessive autophagosome accumulation and autophagic degradation blocking are shown to play an important role in KN‐93‐enhanced‐OS cell death. The synergistic anti‐OS efficacy of KN‐93 and nano‐C60 is further revealed in an OS‐xenografted murine model. The results demonstrate that CaMKIIα inhibition, along with the suppression of autophagic degradation, presents a promising strategy for improving the antitumor efficacy of nano‐C60. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is a common malignant cancer in children and adolescents and has a cure rate that has not improved in the last two decades. CYT997 (lexibulin) is a novel potent microtubule-targeting agent with various anticancer activities, such as proliferation inhibition, vascular disruption, and cell cycle arrest and apoptosis induction, in multiple cancers. However, the direct cytotoxic mechanisms of CYT997 have not yet been fully characterized. Methods: We evaluated apoptosis and autophagy in human osteosarcomas after treatment with CYT997 and investigated the underlying mechanisms. To explore relationships, we used the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), PERK inhibitor GSK2606414, ERO1 inhibitor EN460 and mitochondrial targeted protection peptide elamipretide. BALB/c-nu mice were inoculated with 143B tumor cells to investigate the in vivo effect of CYT997. Results: We explored the efficacy and mechanism of CYT997 in osteosarcoma (OS) in vitro and in vivo and demonstrated that CYT997 potently suppresses cell viability and induces apoptosis and autophagy. CYT997 triggered production of ROS and exerted lethal effects via endoplasmic reticulum (ER) stress in OS cells. NAC attenuated these effects. The PERK inhibitor GSK2606414, which can block the ER stress pathway, reduced ROS production and enhanced cell viability. Moreover, activation of ERO1 in the ER stress pathway was responsible for inducing ROS production. ROS produced by the mitochondrial pathway also aggravate ER stress. Protection of mitochondria can reduce apoptosis and autophagy. Finally, CYT997 prominently reduced tumor growth in vivo. Conclusions: This study suggests that CYT997 induces apoptosis and autophagy in OS cells by triggering mutually enhanced ER stress and ROS and may thus be a promising agent against OS. [ABSTRACT FROM AUTHOR]

Schwann cells (SCs) can promote the regeneration of injured peripheral nerves while the clinical application is limited by donor site complications and the inability to generate an ample amount of cells. In this study, we have isolated human eyelid adipose-derived Schwann cells (hE-SCs) from human eyelid adipose tissue and identified the cell phenotype and function. Using immunofluorescence and H &E staining, we detected subtle nerve fibers and SCs in human eyelid adipose tissue. Immunofluorescence staining indicated that hE-SCs expressed glial markers, such as S100, p75NTR GFAP, Sox10 and Krox20. To explore whether hE-SCs promote the regeneration of injured peripheral nerves in vivo, a Balb/c-nu mice model was used in the study, and mice were randomly assigned to five groups: Matrigel; hE-SCs/P0; hE-SCs/P2; hE-FLCs/P2; and Autograft. After 12 weeks, functional and histological assessments of the regenerated nerves showed that sciatic nerve defect was more effectively repaired in the hE-SCs/P2 group which achieved 66.1 ± 6.5% purity, than the other three groups and recovered to similar level to the Autograft group. These results indicated that hE-SCs can promote the regeneration of injured peripheral nerve and the abundant, easily accessible supply of adipose tissue might be a promising source of SCs for peripheral nerve repair. [ABSTRACT FROM AUTHOR]

Background: Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances.Methods: We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel.Results: We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OSMR and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OSMR and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay.Conclusions: These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma. [ABSTRACT FROM AUTHOR]