Erratum: Author correction to "The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway" Acta Pharm Sin B 12 (2022) 1288-1304

[This corrects the article DOI: 10.1016/j.apsb.2021.08.015.].

Application of minimally invasive ultrasonic osteotome in robotic-assisted sacral tumor resection / 中华骨科杂志

Sacral tumors are surgically challenging and at a high risk of complications. In recent years, robotic-assisted resection has been gradually applied in sacral tumors, but it is difficult to remove bone tissue by present robotic instruments, which limits the application of surgical robot in sacral tumor. The present study aimed to explore the application range and therapeutic effect of minimally invasive ultrasonic osteotome in robotic-assisted sacral tumor resection. Eighteen patients underwent robotic-assisted sacral tumor resection in the First Affiliated Hospital of Sun Yat-Sen University from May 2015 to March 2021 by the Da Vinci robotic surgical system. Among them three patients who underwent osteotomy with minimally invasive ultrasonic osteotome were enrolled. There were 2 males and 1 female, aged 24, 32, 71 years, respectively. The tumors included 2 schwannomas and 1 ganglioneuroma. The operation time, bleeding volume and postoperative hospitalization days were recorded. The recurrence and complications were evaluated during follow-up. The operative time of the 3 patients was 80, 240 and 300 minutes, and the intraoperative bleeding volume was 30, 30 and 100 ml. Complete resection was performed in 2 cases and intralesional resection in 1 case. The postoperative hospital stay was 5, 3 and 7 days respectively. The follow-up time was 58, 17 and 31 months respectively. No tumor recurrence was found during the follow-up. As regards complications, only one patient had left foot pain after operation, and there were no other intraoperative or postoperative complications. The therapeutic advantages of ultrasonic osteotome combined with the Da Vinci robotic surgical system can achieve precise osteotomy, reduce intraoperative bleeding and accelerate postoperative recovery for certain patients with sacral tumors.

The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.

Comparative Study between Low-dose Chemotherapy and Surgery for Isolated Eosinophilic Granuloma Bone Lesions in Children / 中山大学学报(医学科学版)

[Objective]To comprehensively compare the feasibility of three different treatment strategies consisting of low-dose chemotherapy(LDC),surgery and surgery with adjuvant low-dose chemotherapy(SLDC)for children with solitary bone lesions of eosinophilic granuloma(SBL-EG).[Methods]We retrospectively reviewed the records of 149 pediatric patients with SBL-EG at our institutions from 2002 to 2014. Our study included 86 patients who received LDC ,33 patients who received surgery and 30 patients who received SLDC. The duration of hospital stay ,time to symptom relief,recovery time,cost,complications and relapse-free sur-vival(RFS)of each strategy were analyzed.[Results]Hospital stay,time to symptom relief,recovery time and cost in the LDC group were significantly shorter or less than those in the surgery or SLDC group (P 0.05). Chemotherapy-related adverse events in the LDC and SLDC groups included nausea(8.62%),aminotransferase elevation(7.76%),slight hair loss(4.31%), immunity decline (21.55%),growth retardation (10.34%) and moon face (7.76%). LDC and SLDC treatment resulted in a significantly longer RFS (147 months and 126 months ,respectively) than surgery alone (114 months)(P = 0.005 and 0.019 , respectively). However ,there was no statistically significant difference in RFS between the LDC and SLDC groups (P = 0.732).[Conclusions]Compared with surgery or SLDC,LDC appears to promote more rapid recovery,less invasion,increase safety and eco-nomic treatment strategy for pediatric patients with SBL-EG.

The expression level of MAGEA in osteosarcoma and its association with prognosis / 实用医学杂志

Objective To investigate the expression level and clinical significance of melanoma antigen gene A (MAGEA) in osteosarcoma patients. Methods Compare gene expression profiles in osteosarcoma cell lines and osteoblasts with gene microarrays. Validation of differentially expressed genes was carried out by real-time polymerase chain reaction analysis. Corresponding protein levels were measures by Western blot analysis in osteosarcoma cell lines and by immunohistochemistry in osteosarcoma tissues. The staining intensity of immuno-histochemistry was correlated with clinical outcome , and its prognostic significance was analyzed. Results Sev-eral genes belonging to MAGEA increased significantly in all osteosarcoma cell lines and tumor tissue , but not in normal osteoblast cell. Patients with MAGEA expression has higher risk of lung metastasis (relative risk 2.79, 95% confidence interval, 1.12-6.93; P = 0.028) and lower five-year survival rates (39.6% ± 8.4% vs. 80% ± 8.9%, P = 0.01) compared with patients without MAGEA expression. Conclusions The expression of MAGEA increased in osteosarcoma , which inversely correlating with outcome of osteosarcoma patients.

Relationships between quality of life and functional status in patients with malignant bone tumors / 现代临床护理

Objective To explore the relationships of quality of life ( QOL ) and functional status in patients with malignant bone tumors after operation. Methods European organization for research and treatment of cancer quality of life questionnaire C30 (EORTC-QLQ-C30), social support revalued scale (SSRS) and Karnofsky performance scale (KPS) were used to investigate the levels of QOL, social support and functional status. The correlations between them were explored. Results The overall score by QOL was (58.33 ± 18.94). The score by KPS was positively related to somatic function, role function, social function, and general health status (P<0.01), but negatively related to tiredness, pains, insomnia and financial burden (P<0.01). Conclusions The QOL in patients with malignant bone tumors after operation is at a lower level and the function is at a medium level. Nurses should assess the function and make out interventional measures for them so as to improve their QOL.

Intracellular signaling mechanisms pharmacological action of Jasminum amplexicaule Buch.-Ham. [Oleaceae] on gastrointestinal secretion

Jasminum amplexicaule Buch.-Ham. [Oleaceae] has been commonly used in the traditional medicine in dysentery, diarrhoea and bellyache in China. In the present work, the methanol extract of Jasminum amplexicaule [JME] was examined for pharmacology on human colonic epithelial cell line T84 by the short-circuit current technique. The results showed that pretreatment of T84 cells with JME produced a concentration-dependent [0-1000 g/ml. EC50 = 0.055 mg/ml] inhibition effect on adrenalin [Adr.]-induced Cl- secretion. The maximal response was observed at 200 microg/ml. It has been demonstrated that JME has a direct effect on the enterocyte. Our results also demonstrated that the JME exerted inhibitory effect on gastrointestinal Cl- secretion that effected by acting on basolateral beta-adrenoreceptors. These results suggest that the Chinese traditional medicine of JME can be used for the treatment of acute diarrhea and bellyache

Role of SCUBE3 in promoting osteosarcoma cell growth and its association with prognosis / 南方医科大学学报

<p><b>OBJECTIVE</b>To detect the expression of SCUBE3 in human osteosarcoma cell lines and surgical specimens of osteosarcomas and investigate its association with the patients' prognosis.</p><p><b>METHODS</b>The expression of SCUBE3 protein was detected in 5 osteosarcoma cell lines using Western blotting. CCK8 assay was used to assess the effect of SCUBE3 suppression mediated by two specific small interfering RNAs (siRNAs) on the proliferation of U2OS osteosarcoma cells, and the cell cycle changes were detected using flow cytometry. Immunohistochemistry was performed to detect the expression of SCUBE3 in 60 osteosarcoma tissues, and Kaplan-Meier method was performed for survival analysis of the patients.</p><p><b>RESULTS</b>Compared with osteoblast hFOB1.19 cells, the osteosarcoma cell lines all showed significantly higher expressions of SCUBE3. In U2OS cells, suppression of SCUBE3 expression by siRNA significantly inhibited the cell proliferation (P<0.05). Kaplan-Meier survival analysis indicated that patients with high SCUBE3 expression had worse prognosis than those with low SCUBE3 expression (P=0.036).</p><p><b>CONCLUSION</b>SCUBE3 is up-regulated in the 5 osteosarcoma cell lines and in primary osteosarcoma tissues to promote the proliferation of osteosarcoma cells. A high SCUBE3 expression in osteosarcoma tissues is associated with a poor prognosis of the patients, suggesting that SCUBE3 can serve as a potential therapeutic target for osteosarcoma.</p>

Cinobufagin-induced apoptosis in osteosarcoma cells in vitro / 中华骨科杂志

Objective To study the growth inhibition,apoptosis induction effects of cinobufagin(CB)on human osteosarcoma(OS) cell line U2OS,MG63 and SaO2 in vitro and the underlying mechanism of action of cinobufagin in OS cells.Methods Cell viability was assessed by MTT assay.Cell-cycle status,apoptosis-inducing effects were evaluated by flow cytometry,fluorescent staining and DNA fragmentation assays.Inhibitors of apoptosis proteins (IAPs) and Bcl-2 family proteins including Bax,cleaved-PARP,xIAP,cIAP-1,survivin and p65 were tested by Western blot.Results MTT assay showed that CB could inhibited the growth of U2OS,MG63 and SaO2 cells in a dose-and time-dependent manner.The 48 h IC50 of CB on U2OS,MG63 and SaO2 cells were (104.83± 16.96) nmol/L,(47.07±7.5) nmol/L,and (136.72±10.08) nmol/L respectively.The induction of G2/M cell-cycle arrest was seen in the cells treated with CB.After cells were cultured for 12 h in the presence of 100 nmol/L CB,the percentages of cells in the G0/G1 phase were decreased,while G2/M phase were increased in U2OS,MG63 and SaOS2 cells,respectively.The results showed CB inhibited the proliferation of osteosarcoma cells through blocking the cell cycle in G2/M phase.Induction of apoptosis was confirmed by Hoechst 33258 and Annexin V/PI staining.After treating with 100 nmol/L CB for 48 h,the extents of apoptosis were 33.6％±6.4％,36.4％±7.8％ and 29.3％±5.1％,respectively.These results indicate that the anti-tumor activity of cinobufagin in osteosarcoma cells was due to a G2/M cell cycle arrest and apoptosis inducing effect.Western blot showed that CB could induce the apoptosis related family proteins Bax,cleaved-PARP up-regulation,xIAP,cIAP-1,survivin and p65 downregulation in OS cells.Conclusion CB can inhibit the cell viability and induce G2/M cell cycle arrest and apoptosis in U2OS,MG63 and SaO2 cells.The apoptosis-inducing effect of CB is confirmed by the regulation of apoptosis related proteins IAPs and Bcl-2 in vitro.

Expression of chemokine CXCL14 in primary osteosarcoma and its association with prognosis / 南方医科大学学报

<p><b>OBJECTIVE</b>To detect the expression of CXCL14 in human osteosarcoma cell lines and tissues and investigate its association with the prognosis of the patients.</p><p><b>METHODS</b>RT-PCR, enzyme-linked immunosorbent assay (ELISA) and real-time PCR were used to detect the expression of CXCL14 in 4 osteosarcoma cell lines and in 40 pairs of osteosarcoma tissues and adjacent muscular tissues. CCK8 assay and colony formation assay was used to assess the effect of CXCL14 suppression mediated by two specific siRNAs on the proliferation of U2OS osteosarcoma cells. Immunohistochemistry was performed to detect the expression of CXCL14 in 58 osteosarcoma tissues, and Kaplan-Meier method and log-rank test were performed for survival analysis of the patients.</p><p><b>RESULTS</b>Significant up-regulation of CXCL14 expression was found in the osteosarcoma cell lines and in osteosarcoma tissues compared with the adjacent muscles (P<0.01). In U2OS cell, suppression of CXCL14 expression by siRNA significantly inhibited the cell proliferation (P<0.01) and colony formation rate (P<0.05). Kaplan-Meier survival analysis indicated that patients with high CXCL14 expression had worse prognosis than those with low CXCL14 expression (P=0.02).</p><p><b>CONCLUSION</b>CXCL14 is up-regulated in both osteosarcoma cell lines and primary osteosarcoma tissues to promote the proliferation of osteosarcoma cells. A high CXCL14 expression in osteosarcoma tissues is associated with a poor prognosis, suggesting the that CXCL14 serve as a potential therapeutic target for osteosarcoma.</p>

The value of glycogen synthase kinase-3β in the target therapy of osteosarcoma / 中华骨科杂志

Objective To study the affect and the related molecular mechanism of glycogen synthase kinase-3β in the proliferation of osteosarcomaand its value in the target therapy of osteosarcoma.Methods The expression level of p-GSK-3β(Ser9)and GSK-3β were detected in human osteoblast cell and osteosarcoma cells by western blot.Observe the effect of GSK-3β inhibitors and siRNA interference on the GSK-3β regulate osteosarcoma cells using apoptosis protein chip.Evaluate the valueof GSK-3β target therapy on osteosarcoma in vivo.Results The expression level of p-GSK-3β (Ser9)was lower in osteosarcoma cells.LiCL,GSK inhibitor Ⅸ,siRNA knockdown could inhibit the cell viability and up-regulated the apoptosis-related protein cleaved-caspase3.The results of the protein array showed that downstream proteins of NF-κB downregulated significantly.The results were validated by western blot,while the downregulation of p-Iκ-Bα and nuclear NF-κB p65 were also observed after LiCL treatment.Inhibition of GSK-3β by either LiCl or specific siRNA resulted in a significant reduction of NF-κB luciferase reporter activity.Furthermore,the NF-κB luciferase reporter activity was significantly increased in CA cell lines,but not in KD cell lines.By contrast,NF-κB-luciferase reporter activity was significantly decreased in stably GSK-3β knockdown cells.GSK3β inhibitor LiCL and shRNA knock down demonstrated a strong cytotoxicity effect on osteosarcoma cells in vivo.Conclusion GSK-3β is in the state of relative active in osteosarcoma in osteosarcoma and important in cell proliferation.GSK-3β regulates cell survival partially through the NF-κB pathway.It is a promising therapeutic target in osteosarcoma.

Designing and application of continuous health education model / 现代临床护理

Objective To evaluate the effect of continuity of health education model for patients undergoing bone cancer during the first chemotherapy.Methods This model was designed based on KAP(Knowledge,Attitude or Belief,Practice) theory,literature review and questionnaire and performed in 103 bone cancer patients during the first chemotherapy.Results All the patients were assessed,with the founding that the pass rate of knowledge test,treatment compliance and degree of satisfaction were increased significantly(all P<0.05).Conclusions The health education model could help patients learn knowledge about bone cancer,build health behavior and deal with complications.Additionally,it improves the pass rate of knowledge test,satisfaction, and compliance.

Effect and mechanism of quercetin on proliferation and apoptosis of human osteosarcoma cell U-2OS/MTX300 / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effect and mechanisms of quercetin (Qu) on proliferation and apoptosis of human methotrexate resistant osteosarcoma cell U-2OS/MTX300.</p><p><b>METHOD</b>MTT assay was used to observe cell proliferation. The apoptosis was examined by using Annexin V/PI staining. Western blot of mitochondrial membrane potential and cytochrome c were used to detect mitochondria spoptosis pathway. The protein expressions related to Akt pathway was detected by continuous activated Akt transient transfection and western blot.</p><p><b>RESULT</b>Qu can obviously inhibit the growth of human MTX resistant osteosarcoma cell U-2OS/MTX300 cells in a dose- and time-dependent manner. Annexin V/PI staining showed obvious cell apoptosis. Reduction of mitochondrial membrane potential, release of mitochondrial cytochrome c to cytosol and dephoshorylation of Akt were observed after Qu treatment.</p><p><b>CONCLUSION</b>Qu can inhibit proliferation and induce apoptosis of human MTX resistant osteosarcoma cell U-2OS/MTX300, which may be related with mitochondrial apoptosis pathway and Akt activity.</p>

Survival analysis of 311 patients with osteosarcoma of the extremities treated in a single institute / 中华骨科杂志

Objective To investigate treatment and prognosis of patients with osteosarcoma of the extremities.Methods A total of 311 patients with osteosarcoma of the extremities,who had undergone treatment in our institute from 1998 to 2008,were enrolled in this retrospective study.Kaplan-Meier survival curve and Cox regression model were used to analyze the correlation between survival rate and variables including patients' demographics,chemotherapy,surgery,complications,and tumor metastasis.Results Among 311 patients,there were 206 males and 105 females,aged from 5 to 56 years (average,18.6 years).A total of 282 patients underwent aggressive or radical surgery,including 149 cases of limb salvage surgery and 133 cases of amputation surgery.One hundred and five patients underwent standard chemotherapy and 206 patients underwent non-standard chemotherapy.The 5-year survival rate was 57.4％ in patients treated with standard chemotherapy,36.3％ in patients treated with non-standard chemotherapy,16.8％ in patients with lung metastasis,50.7％ in patients without lung metastasis,56.6％ in patients who underwent limb salvage surgery,31.8％ in patients who underwent amputation surgery,44.6％ in patients with Enneking stage Ⅱ B and 33.1％ in patients with Enneking stage Ⅲ.For patients treated by amputation surgery,because non-standard chemotherapy which was performed in most of them and other confounding factors,the 5-year survival rate of them was lower.The Cox regression analysis showed that lung metastasis and non-standard chemotherapy were associated with inferior outcomes.Conclusion Neoadjuvant chemotherapy combined with aggressive or radical surgery could cure about 60％ of patients with osteosarcoma of the extremities.Lung metastasis and non-standard chemotherapy are risk factors that severely affect prognosis.

Biological behaviors of two novel syngeneic human osteosarcoma cell lines / 中华骨科杂志

Objective To characterize and compare the different biological behaviors of two novel human osteosarcoma cell lines, Zos and Zos-M, established respectively from the primary site and the skip metastasis of an osteosarcoma patient. Methods Two novel human osteosarcoma cell lines, Zos and Zos-M,were developed using tissue plant culture method. The vitro examinations included observations of morphology, analysis of karyotype and cell cycle, calculation of doubling time and growth curve, detection of osteoblastic markers and matrigel invasion assay. Subcutaneous, intratibial and intravenous inoculations into nude mice were performed to study the in vivo tumorigenicity and metastatic potentials of both cell lines.MTT were used to detect sensitivity of the cell lines to chemotherapeutic drugs. RT-PCR was performed to assess the expression of and some metastasis-related genes. Results Both cell lines proliferated actively and remained stable for more than 100 passages in vitro without interruption. The morphology and expression of osteoblastic markers of Zos and Zos-M were conformed to the characteristic of osteosarcoma. The karyotype analysis displayed aneuploidy and various structural abnormalities. The population doubling time of Zos and Zos-M were 33.65 h and 31.58 h respectively. Both cell lines were less sensitive to the current chemotherapy protocols compared to U-2OS. Zos and Zos-M were 100% tumorigenic by subcutaneous and othotopic injection. 37.5% of nude mice injected Zos-M and none of nude mice injected Zos developed lung metastasis after intravenous injection. The comparison of the expression patterns of some metastasis-related genes revealed that the decreased expression of cadherin-11 in Zos-M may correlate with a high potential of metastases. Conclusion The two novel established human osteosarcoma cell lines, Zos and Zos-M and related animal models could serve as models for the study of drug resistance and screening of new therapeutics for osteosarcoma. In addition, the study also provide tools for the study of metastasis because the same genetic background and different potential of metastasis of Zos and Zos-M.

Medial gastrocnemius muscle transferring reconstruction the patella tendon with long following-up / 中华显微外科杂志

Objective To evaluate the long following-up outcome of the medial gastrocnemius muscle transferring reconstruction the patella tendon after the wide resection of aggressive bone tumors in the proximal tibia. Methods With the 69 patients of the osteogenetic sarcoma in the proximal tibia were treated with the wide resection and reconstruction the patella tendon. After the long following up the knee extensor,function and complications were evaluated. Results With the 69 patients, the 45 survival patients were followed up for the average 68.6 (24-128) months. The local recurrence rate was 8.7%(6/69). The strength of knee extending was in the average of grade 4.2(3.6-5.0), the degree of knee flexion was in the average of 95°(75°-135°), the degree of knee extension was in the average of-2°(0°-12°), the knees of five patients cannot fully extension. The MSTS functional score was in the average of 77% (23.1/30). Conclusion During the limb salvage of the proximal tibial aggressive bone tumors, the medial gastrocnemius muscle transferring reconstruction the patella tendon could offer the knee extension strength; improve the soft tissue coverage and functional results.

A clinical-radiologic-pathologic analysis of telangiectatic osteosarcoma / 中华放射学杂志

Objective To study the clinical, radiologic and pathologic characteristics and diagnostic methods of telangiectatic osteosarcoma for further improving the diagnostic ability.Methods The data of 10 patients with histologically proved telangiectatic osteosarcomas were retrospectively reviewed, and the clinical, radiologic and pathologic characteristics were further analysed in combination with the literature.All 10 patients were examined with X-ray and MRI, and 2 patients with CT.Results Telangiectatie osteosarcomas originated from inferior femur in 5 patients, femur neck in 1 patients, superior humerus in 2 patients and superior segment of tibia in 2 patients.The lesions showed osteolytic bone destruction on X-ray films (n = 10) and CT images ( n = 2), with mild bone expansion in 4 patients.The majority of the edge of the destroyed bone areas was unclear but without sclerotic rim.There were Codman's triangle and soft tissue mass in each patient but no obvious neoplastic bone forming.On MRI, all the lesions were mostly or completely constituted by the multiple cysts with periostnal reaction, and several scatteredly smaller liquid-liquid levels were found within cystic cavity in 7 patients.In all 10 cases, there were pathologic hemocoele similar to aneurysmal bone cysts (ABC), but malignant tumor cells and some neoplastic bones were found in cystic walls or septations.Only a small number of neoplastic bone tissue were seen by microscopy in 6 patients.Conclusions The radio-pathologic characteristics of telangiectatic osteosarcoma include the similar imaging findings of ABC, the common growth patterns of malignant tumors,and the pathologic hemocoele, malignant tumor cells within cystic wails or septations.The comprehensive analysis of clinical, radiologic and pathological data may help clinicans to make a correct diagnosis for telangiectatic nsteosareoma.

Change of serum osteocalcin level in the bone transplantation / 中国病理生理杂志

AIM: To detect serum osteocalcin level during bone transplantation.METHODS: The animal model of the dog's bone transplantation was established.15 dogs were randomly divided into three groups: irradiation,non-irradiation and bone morphogenetic protein(BMP)-adding group.The allografts bones were treated by cryopreservation and lyophilization,respectively.The animal models were constructed by resecting 2 cm diaphysis and periosteam from the middle pane of both radius of the dogs and transplantation bone were fixed by triargle needle.X-ray examination was taken on the operating day and 1 month,3 months,5 months after operation,respectively.The serum osteocalcin level was detected preoperation,2 weeks,4 weeks,6 weeks,8 weeks and 10 weeks after operation.RESULTS: The level of serum osteocalcin significantly changed in the bone transplantation before and after operation.BMP made an effect on the changes of BGP.CONCLUSIONS: Serum osteocalcin is a peculiar sensitive and convenient biochemical index that reflects metabolism of bone transplantation.More over,it has some importance for differently processed allografts of bone.BMP increases the content of BGP in the serum and accelerates the bone formation.