Population Pharmacokinetics of High-dose Methotrexate After Intravenous Administration in Chinese Osteosarcoma Patients from a Single Institution

Background:High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma.The plasma concentration of MTX is closely related to effi...     

Emodin induces apoptosis of human osteosarcoma cells via mitochondria- and endoplasmic reticulum stress-related pathways

Aim: Emodin showed anti-cancer activity against multiple human malignant tumors by inducing apoptosis. However, the apoptotic inducing effect against human osteosarcoma and related mechanism are still not studied. This study was aimed to investigate them. Methods: Emodin was used to incubate human OS cell U2OS cells at serially diluted concentrations. Hoechst staining was used to evaluate apoptosis; flow cytometry was applied to assess the collapse of mitochondrial membrane potential (MMP); intracellular ROS generation was detected by DCFH-DA staining; endoplasmic reticulum stress activation was examined by western blotting. Results: Cell apoptosis of U2OS cells was induced by emodin incubation in a concentration-dependent manner; MMP collapse and ROS generation were identified at starting concentration of 80 μmol/L of emodin in a concentration-dependent manner. ER stress activation was found at beginning concentration of 40 μmol/L of emodin. The MMP collapse was inhibited while the ER stress was not inhibited by NAC administration. Conclusions: Emodin induces death of human osteosarcoma cells by initiating ROS-dependent mitochondria-induced and ROS-independent ER stress-induced apoptosis.     

Single nucleotide polymorphisms of HER2 related to osteosarcoma susceptibility

Aims: The purpose of this study was to investigate the correlation between single necleotide polymorphisms (SNPs) of human epidermal growth factor receptor-2 (HER2) gene with osteosarcoma susceptibility in Chinese Han population. Methods: 90 patients with osteosarcoma and 100 healthy controls who were frequency-matched with the former by age and gender were enrolled for a case-control study. 5 SNPs of HER2, namely rs2952155, rs1810132, rs2952156, rs1136201 and rs1058808, were tested by Sequenom time of flight mass spectrometry technique. The linkage disequilibrium and haplotype were analyzed using haploview software. The risk intensity of osteosarcoma was expressed by odds ratio (OR) with 95% confidence interval (CI) which was calculated by chi-squared text. Hardy-Weinberg equilibrium (HWE) was also evaluated by chi-squared text. Results: HER2 gene rs1136201 and rs1058808 polymorphisms were associated with the increased risk of osteosarcoma (P=0.04 and 0.02, respectively). Allele G in rs1136201 was 1.67 higher risk for osteosarcoma in cases than the control group (OR=1.67, 95% CI=1.11-2.51) and G allele of rs1058808 polymorphism also significantly increased osteosarcoma susceptibility (OR=2.06, 95% CI=1.27-3.22). The haplotype analysis showed that haplotype C-T-G-G might be a susceptible haplotype to osteosarcoma (OR=1.74, 95% CI=1.01-3.00). HWE test was eligible in controls (P>0.05). Conclusion: HER2 gene rs1136201 and rs1058808 polymorphisms and haplotype C-T-G-G may be related to osteosarcoma susceptibility in Chinese Han population, indicating that the interaction of gene polrmorphism plays an role in osteosarcoma risk.     

MicroRNA-370 directly targets FOXM1 to inhibit cell growth and metastasis in osteosarcoma cells

MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs, which play a critical role in regulating varieties of the biological and pathologic processes. Several reports have indicated that miR-370 acts as a tumor suppressor in varieties of tumors. However, the roles of miR-370 in osteosarcoma have not been reported. In this study, our objective was to explore the biological functions and its molecular mechanism of miR-370 in osteosarcoma cell lines, finding a therapeutic target of osteosarcoma. Our data demonstrated that miR-370 was evidently reduced in osteosarcoma cell lines, whereas FOXM1 expression was markedly increased. Up-regulation of miR-370 suppressed proliferation, arrested cell cycle and induced apoptosis in osteosarcoma cells. Besides, invasion and EMT of osteosarcoma cells was also inhibited by introduction of miR-370. Next, we found that FOXM1 expression was significantly reduced by up-regulation of miR-370. Bioinformatics analysis predicted that the FOXM1 was a potential target gene of miR-370. Luciferase reporter assay further confirmed that miR-370 could directly target the 3’ UTR of FOXM1. Overexpression of FOXM1 in osteosarcoma cells transfected with miR-370 mimic partially reversed the effects of miR-370. In conclusion, miR-370 inhibited cell growth and metastasis in osteosarcoma cells by down-regulation of FOXM1.     

Distinctive Head and Neck Bone and Soft Tissue Neoplasms

Benign and malignant primary bone and soft tissue lesions of the head and neck are rare. The uncommon nature of these tumors, combined with the complex anatomy of the head and neck, pose diagnostic challenges to pathologists. This article describes the pertinent clinical, radiographic, and pathologic features of selected bone and soft tissue tumors involving the head and neck region, including angiofibroma, glomangiopericytoma, rhabdomyosarcoma, biphenotypic sinonasal sarcoma, chordoma, chondrosarcoma, and osteosarcoma. Emphasis is placed on key diagnostic pitfalls, differential diagnosis, and the importance of correlating clinical and radiographic information, particularly for tumors involving bone.     

Primary vertebral osteosarcoma: Five cases

Primary vertebral osteosarcoma is a rare type of osteosarcoma, differing from the appendicular forms by an incidence peak occurring at a higher age and a poorer prognosis, due to the difficulties of the surgical treatment. We present five cases of histologically proven primary vertebral osteosarcomas followed in our institution between 2004 and 2012. They allow to illustrate some essential radiologic features, useful to evoke this rare entity.     

OSTEOSARCOMA AS A SECOND MALIGNANCY AFTER TREATMENT FOR NEUROBLASTOMA

A 4-month old girl was diagnosed as having stage IV neuroblastoma of the right adrenal gland. Preoperative chemotherapy was given, followed by local surgical excision. Postoperatively, irradiation of the tumor bed and adjuvant chemotherapy was given for 11 months. Nine years after cessation of chemotherapy, the patient developed left hip-joint pain. Biopsy of the ischium showed chondroblastic osteosarcoma. Limb salvage surgery was performed after preoperative chemotherapy. Postoperatively, adjuvant chemotherapy was given for 14 months. Twenty-two months after treatment for the secondary osteosarcoma, the patient has been remained in disease-free condition without any evidence of relapse. A second osteosarcoma occurring outside the radiation field after treatment for neuroblastoma is quite rare. This unusual case emphasized the need for close monitoring for development of second malignant neoplasms in survivors of neuroblastoma even in the absence of a known predisposing factor, such as radiation therapy.     

Mir-664 promotes osteosarcoma cells proliferation via downregulating of FOXO4

BackgroundUncontrol cell growth and proliferation is acknowledged to responsible for cancer-related deaths by disorganizing the balance of growth promotion and growth limitation. Aberrant expression of microRNA play essential roles in cancer development, leads to cell proliferation, growth and survival, and promotes the development of various human tumors, including osteosarcoma. Elucidating the molecular mechanism of this abnormality in osteosarcoma carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy.MethodsThe expression of miR-664 in osteosarcoma cell lines and osteosarcoma tissues was examined using real-time PCR. The effects of miR-664 on osteosarcoma cell proliferation were evaluated by 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation and Anchorage-independent growth ability assay. The effect of miR-664 on FOXO4 was determine by luciferase assays and western blot assay.ResultsThe expression of miR-664 was markedly upregulated in osteosarcoma cell lines and tissues, and upregulation of miR-664 enhanced, whereas downregulation of miR-664 inhibited the proliferation of osteosarcoma cells in vivo. Furthermore, using bioinformatics and biological approaches, we showed that miR-664 directly targeted and suppressed the expression of tumor suppressors FOXO4.ConclusionsOur findings suggest that miR-664 functions as an oncogene miRNA and has an important role in promoting human osteosarcoma cell proliferation by suppressing FOXO4 expression. These data suggests that miR-664 may represent a novel therapeutic target of microRNA-mediated suppression of cell proliferation in osteosarcoma.     

Activation of unfolded protein response protects osteosarcoma cells from cisplatin-induced apoptosis through NF-κB pathway

The aim of this study was to uncover that unfolded protein response (UPR) contributed to the development of cisplatin resistance in osteosarcoma. MG-63 cells and SaOS-2 cells were exposed to cisplatin at presence or absence of 4-phenylbutyrayte (4-pba) and then analyzed by MTT assay and flow cytometry to determine the cell survival rates and apoptosis. Levels of glucose regulated protein 78KD (GRP78), C/EBP homologus protein (CHOP), cytoplasmic and nuclear NF-κB were detected by Western blot. Further, MG-63 cells and SaOS-2 cells were subjected to cisplatin with or without Bay 11-7082, a well-known inhibitor of NF-κB. After that, MTT assay and flow cytometry were used to determine the cell survival rates and apoptosis. Cisplatin and 4-PBA co-treatment significantly enhanced the cell apoptosis. Administration of cisplatin substantially increased the levels of GRP78 and CHOP. Moreover, mechanistic investigation uncovered that cisplatin promoted the levels of nuclear NF-κB whereas 4-PBA administration suppressed the cisplatin-induced accumulation of nuclear NF-κB level in osteosarcoma cells. Cisplatin combined with Bay 11-7082 obviously augmented MG-63 cells and SaOS-2 cells apoptosis when compared to that in osteosarcoma cells treated by cisplatin alone. Taken together, our data show that UPR protects osteosarcoma from cisplatin-mediated apoptosis through activation of NF-κB pathway. Therefore, targeting UPR may be a potential strategy to improve the osteosarcoma therapy.