Reduced recurrence rate and comparable functionality after wide resection and reverse total shoulder arthroplasty with allograft-prosthetic composite versus curettage for proximal humeral giant cell tumor: a multicenter retrospective study.

BACKGROUND: Giant cell tumors of bone (GCTBs) are rare, aggressive tumors, and the proximal humerus is a relatively rare location for GCTBs; limited evidence exists on which surgical approaches and reconstruction techniques are optimal. In the largest case series to date, we evaluated the recurrence rate of proximal humeral GCTBs and the functional outcomes of different resection and reconstruction options in this multicenter study. METHODS: All 51 patients included in this study received initial surgical treatment for proximal humeral GCTBs from January 2007 to December 2020, with a minimum 2-year follow-up period. Local recurrence and functional outcomes were statistically analyzed in relation to demographic, clinical, and primary surgical variables. Functional outcomes were reported by patients and were assessed by the Musculoskeletal Tumor Society score and QuickDASH instrument (shortened version of the Disabilities of the Arm, Shoulder and Hand instrument). RESULTS: The mean follow-up period was 81.5 months (range, 30-191 months), and the overall recurrence rate was 17.6% (9 of 51 patients). The majority of recurrences (n = 7) occurred in the first 2 years of follow-up. The intralesional curettage group (n = 23) showed a statistically significant difference in the recurrence rate compared with the en bloc resection group (n = 28) (34.8% vs. 3.6%, P = .007). Among shoulders receiving en bloc resection, 16 were reconstructed with hemiarthroplasty; 8, reverse total shoulder arthroplasty (rTSA) with allograft-prosthetic composite (APC) reconstruction; and 4, arthrodesis. On the basis of intention-to-treat analysis, the mean functional Musculoskeletal Tumor Society scores of the groups undergoing curettage, rTSA with APC, hemiarthroplasty, and arthrodesis were 26.0 ± 3.1, 26.0 ± 1.7, 20.3 ± 2.8, and 22.5 ± 1.3, respectively (P < .001 [with P < .001 for curettage vs. hemiarthroplasty and P = .004 for rTSA with APC vs. hemiarthroplasty]) and the mean QuickDASH scores were 14.0 ± 11.0, 11.6 ± 4.5, 33.1 ± 11.8, and 21.6 ± 4.7, respectively (P < .001 [with P < .001 for curettage vs. hemiarthroplasty and P = .003 for rTSA with APC vs. hemiarthroplasty]). CONCLUSIONS: On the basis of our data, en bloc resection followed by reverse shoulder arthroplasty showed a lower recurrence rate and no significant difference in functional outcome scores for proximal humeral GCTBs compared with intralesional curettage. Therefore, we believe that rTSA with APC may be reasonable for the initial treatment of proximal humeral GCTBs.

Revision surgeries for tumor endoprostheses around the knee joint: a mid-long-term follow-up of 20 cases.

BACKGROUND: Tumor endoprostheses of the knee joint after limb salvage surgery is associated with high rates of complications, which has introduced great challenges to a delayed revision surgery. The aim of the study was to summarize the failures, functional outcomes and prosthetic survival in revision tumor endoprostheses of the knee joint. METHODS: The clinical data of 20 patients with malignant tumors who received prosthetic revisions after limb salvage surgery from January, 2000 until January, 2018 were retrospectively reviewed. The cohort was constituted of 11 male and 9 female patients with a mean age of 34.1 years (range, 16 to 66 years). Infection cases received two-stage revisions after removing prostheses initially, while all other cases received one-stage revisions. Revision reasons and complications were well documented and analyzed. RESULTS: All patients received complete follow-up with a mean time of 64.7 months (range, 27 to 155 months). A total of 6 (6/20, 30.0%) patients experienced a second complication after revision surgery, of whom, one patient with deep infection experienced repeated infections after prosthetic revision and received amputation surgery; one patient revised of prosthetic fracture experienced an infection and received a second-stage infection revision; one case revised of prosthetic loosening had deep infection receiving anti-infective therapy with prostheses still in position; one case having wound complication healed after receiving two times of debridement surgery; one MBGCT patient experienced a second aseptic loosening 6 years after the initial loosening thus undergoing a second revision; a recurrent osteosarcoma patient died of pulmonary metastasis 3 years after revision surgery. Kaplan-Meier survival curve indicated a 5-year survival rate of initial prostheses was 75%. The Musculoskeletal Tumor Society (MSTS-93) score [20.9 (range, 15 to 27 scores)] at 1 year after revision surgeries was significantly improved (p < 0.001) when compared with the score [17.2 (range, 13 to 21 scores)] before revisions. CONCLUSION: Prosthetic mechanical problems, aseptic loosening and infections were primary reasons for revisions after tumor endoprostheses of the knee joint. Although revision surgeries were complicated while still associated with high risk of failure, which remains the remedy strategy for limb salvage and functional recovery in those patients.

ML216-Induced BLM Helicase Inhibition Sensitizes PCa Cells to the DNA-Crosslinking Agent Cisplatin.

Using standard DNA-damaging medicines with DNA repair inhibitors is a promising anticancer tool to achieve better therapeutic responses and reduce therapy-related side effects. Cell viability assay, neutral comet assay, western blotting (WB), and cell cycle and apoptosis analysis were used to determine the synergistic effect and mechanism of ML216, a Bloom syndrome protein (BLM) helicase inhibitor, and cisplatin (CDDP), a DNA-crosslinking agent, in PCa cells. Based on the online database research, our findings revealed that BLM was substantially expressed in PCa, which is associated with a bad prognosis for PCa patients. The combination of ML216 and CDDP improved the antiproliferative properties of three PCa cell lines. As indicated by the increased production of γH2AX and caspase-3 cleavage, ML216 significantly reduced the DNA damage-induced high expression of BLM, making PC3 more susceptible to apoptosis and DNA damage caused by CDDP. Furthermore, the combination of ML216 and CDDP increased p-Chk1 and p-Chk2 expression. The DNA damage may have triggered the ATR-Chk1 and ATM-Chk2 pathways simultaneously. Our results demonstrated that ML216 and CDDP combination therapy exhibited synergistic effects, and combination chemotherapy could be a novel anticancer tactic.

[An exploratory clinical study of the efficacy and safety of tumor-infiltrating lymphocytes in the treatment of metastatic osteosarcoma].

Objective: To explore the safety and efficacy of tumor-infiltrating lymphocytes (TILs) extracted from tumor tissue in patients with pulmonary metastasis of osteosarcoma, the TILs were amplified in vitro to reach clinical dosage and reinfused to the patients combined with high-dose interleukin 2 (IL-2). Methods: Twelve subjects with pathologically diagnosed osteosarcoma were enrolled from December 2019 to June 20, 2021 in Shanghai General Hospital. All subjects progressed with metastasis after standard chemotherapy and failed multiple lines of treatments. Fresh tumor tissue was obtained from the metastatic site and extracted and amplified by Good Manufacturing Practice (GMP) workshop to produce TILs to clinical treatment dosage (109-1011). High-dose IL-2 (100 000-200 000 U/kg) was administered immediately after autogenous TILs infusion to promote the activation, proliferation and antitumor cytolytic activity in vivo. Adverse events (AE) were graded according to Common Terminology Criteria for Adverse Events (CTCAE) standard and tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results: One patient did not receive treatment due to failure in isolating TILs, total of 11 patients received a single re-infusion of autologous TILs. There were 10 males and 1 female with a median age of 19.9 years (12-33 years). Six of these patients received higher dose levels of 1.0×1010 TILs. The 11 patients were followed-up for 1 to 13 months and tolerated well. The most common adverse events reported were fever (10/11), constipation (3/11) and elevated gamma-glutamyl transferase (GGT) (3/11). The high incidence of fever was due to the IL-2 infusion. All patients experienced a transient drop in lymphocyte count and leukopenia leading to non-myeloid ablative lymphocyte clearance. The AE included grade 4 hematologic toxicity, including 8 cases of lymphocytopenia, 2 cases of neutropenia and 1 case of thrombocytopenia. No AE of neurotoxicity occurred. Of all the 11 patients, 9 patients got stable disease (SD) and 2 patients had progressive disease (PD). The disease control rate was 9/11. The median duration of SD was more than 4 months, and the maximum tumor volume decreased by close to 20%. Patient number 9 had sustained SD status for more than 6 months. Conclusions: TILs with in vitro expansion ability could be isolated from tumor tissues of advanced osteosarcoma patients. TILs amplified and reinfused in vitro have anti-osteosarcoma activity.

Reduction-responsive polypeptide nanomedicines significantly inhibit progression of orthotopic osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor with high metastasis and mortality. Neoadjuvant chemotherapy is an effective therapeutic regimen, but the clinical application is limited by the unsatisfactory efficacies and considerable side effects. In this study, the reduction-responsive polypeptide micelles based on methoxy poly(ethylene glycol)-block-poly(S-tert-butylmercapto-L-cysteine) copolymers (mPEG113-b-PBMLC4, P4M, and mPEG113-b-PBMLC9, P9M) were developed to control the delivery of doxorubicin (DOX) in OS therapy. Compared to free DOX, P4M/DOX and P9M/DOX exhibited 2.6 and 3.5 times increase in the area under the curve of pharmacokinetics, 1.6 and 2.0 times increase in tumor accumulation, and 1.6 and 1.7 times decrease of the distribution in the heart. Moreover, the selective accumulation of micelles, especially P9M/DOX, in tumors induced stronger antitumor effects on both primary and lung metastatic OSs with less systematic toxicity. These micelles with smart responsiveness to intracellular microenvironments are highly promising for the targeted delivery of clinical chemotherapeutic drugs in cancer therapy.

Drug resistance-related microRNAs in osteosarcoma: Translating basic evidence into therapeutic strategies.

Although the application of multiple chemotherapy brought revolutionary changes to improve overall survival of osteosarcoma patients, the existence of multidrug resistance (MDR) has become a great challenge for successful osteosarcoma treatment in recent decades. Substantial studies have revealed various underlying mechanisms of MDR in cancers. As for osteosarcoma, evidence has highlighted that microRNAs (miRNAs) can mediate in the processes of DNA damage response, apoptosis avoidance, autophagy induction, activation of cancer stem cells, and signal transduction. Besides, these drug resistance-related miRNAs showed much promise for serving as candidates for predictive biomarkers of poor outcomes and shorter survival time, and therapeutic targets to reverse drug resistance and overcome treatment refractoriness. This review aims to demonstrate the potential molecular mechanisms of miRNAs-regulated drug resistance in osteosarcoma, and provide insight in translating basic evidence into therapeutic strategies.

Immunogenic cell death in cancer therapy: Present and emerging inducers.

In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of damage-associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD eventually results in long-lasting protective antitumour immunity. Through the exploration of ICD inducers, recent studies have shown that there are many novel modalities with the ability to induce immunogenic cancer cell death. In this review, we mainly discussed and summarized the emerging methods for inducing immunogenic cancer cell death. Concepts and molecular mechanisms relevant to antitumour effects of ICD are also briefly discussed.

Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma.

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.

Antitumor activity of Raddeanin A is mediated by Jun amino-terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A (RA) is an active oleanane-type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose- and time-dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species (ROS) generation and JNK and ERK1/2 activation. Apoptosis induction was evaluated by the activation of caspase-3, caspase-8, and caspase-9 and poly-ADP ribose polymerase (PARP) cleavage. RA-induced cell death was significantly restored by the ROS scavenger glutathione (GSH), the pharmacological inhibitor of JNK SP600125, or specific JNK knockdown by shRNA. Additionally, signal transducer and activator of transcription 3 (STAT3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH, SP600125, and JNK-shRNA. Further investigation showed that STAT3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK/c-Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

Surgical resection and reconstructive techniques using autologous femoral head bone-grafting in treating partial acetabular defects arising from primary pelvic malignant tumors.

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.

Oxymatrine exerts protective effects on osteoarthritis via modulating chondrocyte homoeostasis and suppressing osteoclastogenesis.

Osteoarthritis (OA) is a common degenerative disease characterized by the progressive destruction both articular cartilage and the subchondral bone. The agents that can effectively suppress chondrocyte degradation and subchondral bone loss are crucial for the prevention and treatment of OA. Oxymatrine (OMT) is a natural compound with anti-inflammatory and antitumour properties. We found that OMT exhibited a strong inhibitory effect on LPS-induced chondrocyte inflammation and catabolism. To further support our results, fresh human cartilage explants were treated with LPS to establish an ex vivo degradation model, and the results revealed that OMT inhibited the catabolic events of LPS-stimulated human cartilage and substantially attenuated the degradation of articular cartilage ex vivo. As subchondral bone remodelling is involved in OA progression, and osteoclasts are a unique cell type in bone resorption, we investigated the effects of OMT on osteoclastogenesis, and the results demonstrated that OMT suppresses RANKL-induced osteoclastogenesis by suppressing the RANKL-induced NFATc1 and c-fos signalling pathway in vitro. Further, we found that the anti-inflammatory and anti-osteoclastic effects of oxymatrine are mediated via the inhibition of the NF-κB and MAPK pathways. In animal studies, OMT suppressed the ACLT-induced cartilage degradation, and TUNEL assays further confirmed the protective effect of OMT on chondrocyte apoptosis. MicroCT analysis revealed that OMT had an attenuating effect on ACLT-induced subchondral bone loss in vivo. Taken together, these results show that OMT interferes with the vicious cycle associated with OA and may be a potential therapeutic agent for abnormal subchondral bone loss and cartilage degradation in osteoarthritis.

HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1.

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.

Enzymatic Reaction Generates Biomimic Nanominerals with Superior Bioactivity.

In vivo mineralization is a multistep process involving mineral-protein complexes and various metastable compounds in vertebrates. In this complex process, the minerals produced in the mitochondrial matrix play a critical role in initiating extracellular mineralization. However, the functional mechanisms of the mitochondrial minerals are still a mystery. Herein, an in vitro enzymatic reaction strategy is reported for the generation of biomimic amorphous calcium phosphate (EACP) nanominerals by an alkaline phosphatase (ALP)-catalyzed hydrolysis of adenosine triphosphate (ATP) in a weakly alkalescent aqueous condition (pH 8.0-8.5), which is partially similar to the mitochondrial environment. Significantly, the EACP nanomineral obviously promotes autophagy and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by activating an AMPK related pathway, and displays a high performance in promoting bone regeneration. These results provide in vitro evidence for the effect of ATP on the formation and stabilization of the mineral in the mineralization process, demonstrating a potential strategy for the preparation of the biomimic mineral for treating bone related diseases.

Modified Unilateral Pedicled V-Y Advancement Flap for Scalp Defect Repair.

Reconstruction of scalp defects caused by tumor resection or trauma is very challenging. A majority of the surgeons prefer to use local flap rather than skin graft or free flap for scalp defects repair. The aim of this study is to investigate the technique of modified unilateral pedicled V-Y advancement flap for the reconstruction of scalp defect.A retrospective review was performed in a series of 18 patients who had a modified unilateral pedicled V-Y advancement flap to restore scalp defect from May 2013 to January 2017. Their mean age is 58 (24-78) years. These patients suffered from basal cell carcinoma, seborrhoeic keratosis, squamous cell carcinoma, or trauma on the scalp. All of them underwent preoperative Doppler scanning to identify the scalp arteries and then individually designed. The flap size ranged from 33 × 50 mm to 68 × 105 mm. Patients were followed for an average of 12 months postoperatively (ranged from 6 to 37 months). No major complications occurred, only 2 cases had a minor distal epidermal necrosis or obstruction of venous backflow observed for the first 3 days of the surgery, and they both healed well. Modified unilateral pedicled V-Y flap technique with fairly rapid recovery and acceptable reorientation of hair follicles leads to esthetical outcome and patient satisfaction. Most importantly, no tumor recurrence at the original site during the follow-up period was seen.The modified unilateral pedicled V-Y advancement flap is a simple but efficient technique, particularly suitable for the repair of small and medium size scalp defects with advantages including the safety of the procedure and overall esthetic results like hairline preservation and less scarring when compared to other local flap techniques.

Alternol, a natural compound, exerts an anti-tumour effect on osteosarcoma by modulating of STAT3 and ROS/MAPK signalling pathways.

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.

BRD4 has dual effects on the HMGB1 and NF-κB signalling pathways and is a potential therapeutic target for osteoarthritis.

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-1ß-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.

P-glycoprotein overexpression in bone marrow-derived multipotent stromal cells decreases the risk of steroid-induced osteonecrosis in the femoral head.

P-glycoprotein (P-gp) plays a role in steroid-induced osteonecrosis of the femoral head (ONFH), but the underlying mechanism remains unknown. We hypothesized that P-gp overexpression can prevent ONFH by regulating bone marrow-derived multipotent stromal cell (BMSC) adipogenesis and osteogenesis. BMSCs from Sprague-Dawley rats were transfected with green fluorescent protein (GFP) or the multidrug resistance gene 1 (MDR1) encoding GFP and P-gp. Dexamethasone was used to induce BMSC differentiation. Adipogenesis was determined by measuring peroxisome proliferator-activated receptor (PPAR-γ) expression and the triglyceride level. Osteogenesis was determined by measuring runt-related transcription factor 2 (Runx2) expression and alkaline phosphatase activity. For in vivo experiments, rats were injected with saline, BMSCs expressing GFP (GFP-BMSCs) or BMSCs expressing GFP-P-gp (MDR1-GFP-BMSCs). After dexamethasone induction, adipogenesis was determined by measuring PPAR-γ expression and fatty marrow, whereas osteogenesis was detected by measuring Runx2 expression, trabecular parameters and the mineral apposition rate, followed by evaluation of the incidence of ONFH. Overexpression of P-gp in BMSCs resulted in markedly decreased expression of adipogenic markers and increased expression of osteogenic markers. Compared with rats injected with saline, rats injected with GFP-BMSCs showed reduced ONFH, and the injected GFP-positive BMSCs attached to trabecular surfaces and exhibited an osteoblast-like morphology. Compared with the rats injected with BMSCs expressing GFP alone, rats injected with BMSCs overexpressing GFP and P-gp showed lower adipocytic variables, higher osteogenic variables and lower incidence of ONFH. Overexpression of P-gp inhibited BMSC adipogenesis and promoted osteogenesis, which reduced the incidence of steroid-induced ONFH.

Nanog interact with CDK6 to regulates astrocyte cells proliferation following spinal cord injury.

Previous research had reported transcription factors Nanog expressed in pluripotent embryonic stem cells (ESCS) that played an important role in regulating the cell proliferation. Nanog levels are frequently elevated in ESCS, but the role in the spinal cord was not clear. To examine the biological relevance of Nanog, we studied its properties in spinal cord injury model. The expression of Nanog and PCNA was gradually increased and reached a peak at 3 day by western blot analysis. The expression of Nanog was further analyzed by immunohistochemistry. Double immunofluorescent staining uncovered that Nanog can co-labeled with PCNA and GFAP in the spinal cord tissue. In vitro, Nanog can promote the proliferation of astrocyte cell by Fluorescence Activating Cell Sorter (FACS) and CCK8. Meanwhile, the cell-cycle protein CDK6 could interact with Nanog in the spinal cord tissue. Taken together, these data suggested that both Nanog may play important roles in spinal cord pathophysiology via interact with CDK6.

Gelsolin promotes cell growth and invasion through the upregulation of p-AKT and p-P38 pathway in osteosarcoma.

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.

Palliative treatment of pelvic bone tumors using radioiodine (125I) brachytherapy.

BACKGROUND: Complete resection of pelvic bone tumors, especially recurrent and metastatic ones, is often impossible to achieve using conventional surgery. This study aimed to assess the benefits and adverse effects of computed tomography (CT)-guided radioiodine (125I) brachytherapy for inoperable recurrent and metastatic bone tumors of the pelvis. METHODS: This was a retrospective study of 22 patients with confirmed pelvic bone tumors (10 females and 12 males; 15-84 years; 21 with primary pelvic tumor and one with pelvic metastasis). CT-guided 125I brachytherapy was performed using 9-21 125I seeds (radioactivity of 0.5-0.7 mCi). Seed implantation was validated by postoperative CT scanning. Complications, pain, survival, and CT-estimated tumor size were carried out to evaluate the therapeutic benefits. RESULTS: Postoperative CT scans revealed satisfactory 125I seed implantation, and the radiation dose delivered to 90% of the target area (D90) was higher than the prescription dose (PD). No obvious complications were observed. Pain was reported by 19 of 22 patients, but 17 reported pain relief after implantation. Follow-up ranged 8-27 (median, 19) months. Tumor size was reduced in 11 patients within 1 month after surgery, nine patients showed no change, and tumor size increased in two patients. Finally, 1- and 2-year survival was 81.8 and 45.5%, respectively; 1- and 2-year local tumor control rates were 59.1 and 36.4%, respectively. CONCLUSIONS: 125I seed implantation significantly reduced bone tumor size and relieved pain, with a low complication rate. These findings suggest that 125I brachytherapy treatment could be a useful palliative approach for pelvic bone tumor treatment.