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Disruption of the intervertebral disc extracellular matrix (ECM) is a hallmark of intervertebral disc degeneration (IDD), which is largely attributed to excessive oxidative stress. However, there is a lack of clinically feasible approaches to promote the reconstruction of the disc ECM. Glucagon-like peptide-1 (GLP-1), a safe polypeptide hormone adopted to treat type 2 diabetes mellitus, has shown great potential for relieving oxidative stress-related damage. To our knowledge, this is the first study to reveal that exenatide, a GLP-1 receptor (GLP-1R) agonist, can upregulate disc ECM synthesis and attenuate oxidative stress-induced ECM degradation and IDD. Mechanistically, we found that exenatide inhibited the activation of mitogen-activated protein kinases (MAPK) signaling pathway and the formation of BATF/JUNs heterodimers (an index of activator protein-1 (AP-1) activity). The restoration of MAPK signaling activation reversed the protective effects of exenatide and enhanced downstream BATF/JUNs binding. BATF overexpression was also found to aggravate disc ECM damage, even in the presence of exenatide. In summary, exenatide is an effective agent that regulates ECM anabolic balance and restores disc degeneration by inhibiting MAPK activation and its downstream AP-1 activity. The present study provides a therapeutic rationale for activating the GLP-1 receptor against IDD and establishes the important role of AP-1 activity in the pathogenesis of IDD.

Osteosarcoma is a rare malignant bone-originating tumor that usually occurs in young people. Programmed cell death 1 ligand 1 (PD-L1), an immune checkpoint protein, is highly expressed in osteosarcoma tissues. Several recent studies have indicated that the tumor-related role of PD-L1 in tumors, especially non-plasma membrane (NPM)-localized PD-L1, is not limited to immune regulation in osteosarcoma. Here, mass spectrometry analysis is combined with RNA-seq examination to identify the intracellular binding partners of PD-L1 and elucidate the underlying mechanism of its action. It is found that the NPM-localized PD-L1 interacted with Insulin-like growth factor binding protein-3 (IGFBP3) to promote osteosarcoma tumor growth by activating mTOR signaling. This interaction is enforced after phosphoglyceratekinase1 (PGK1)-mediated PD-L1 phosphorylation. Based on these findings, a phosphorylation-mimicking peptide is designed from PD-L1 and it is encapsulated with a Cyclic RGD (cRGD)-modified red blood cell membrane (RBCM) vesicle (Peptide@cRGD-M). The Peptide@cRGD-M precisely delivers the PD-L1-derived phosphorylation-mimicking peptide into osteosarcoma lesions and significantly promotes its therapeutic effect on the tumor. Therefore, this investigation not only highlights the function of NPM-localized PD-L1, but also uses an engineering approach to synthesize a small molecular peptide capable of inhibiting osteosarcoma growth.

To investigate the mid-term effectiveness of three-dimensional (3D) printed osteotomy guide plate and personalized prosthesis in knee-preserving tumor resection.The clinical data of 12 patients who underwent knee-preserving tumor resection and reconstruction with 3D printed osteotomy guide plate and personalized prosthesis between September 2016 and October 2018 were retrospectively analyzed. There were 7 males and 5 females. The age ranged from 7 to 59 years, with a median of 44.5 years. There were 11 cases of osteosarcoma and 1 case of fibrosarcoma, all of which were Enneking grade ⅡB. The distance from the tumor to the joint surface was 5.5-8.2 cm, with an average of 6.94 cm. Incision healing, tumor recurrence, periprosthetic fracture, and aseptic loosening were observed after operation. The Musculoskeletal Tumor Society (MSTS) scoring system was used to evaluate the function of the patients, and the knee flexion range of motion was measured.The 12 patients were followed up 41-66 months, with an average of 54.5 months. The length of osteotomy ranged from 14 to 26 cm, with an average of 22.08 cm. Except for 2 patients with superficial infection of incision tissue, no deep infection involving the prosthesis occurred, no patient underwent revision surgery because of prosthesis infection. During the follow-up, local recurrence occurred in 2 cases and distant metastasis occurred in 3 cases. The overall disease-free survival rate was 58.3%. Two patients died of lung metastasis, and the overall survival rate was 83.3%. One patient underwent amputation due to local recurrence, and 1 patient underwent total knee arthroplasty due to prosthesis rupture. No aseptic loosening of the prosthesis and periprosthetic fracture occurred during the follow-up, and the overall prosthesis survival rate was 83.3%. At last follow-up, 10 patients obtained satisfactory knee flexion range of motion that ranged from 95° to 125°, with an average of 110°. Two children could not cooperate with early rehabilitation treatment due to pain, and the knee flexion range of motion was not ideal (50°, 75°). All patients achieved acceptable lower limb function with MSTS scores ranged from 26 to 30, with an average of 28. All patients walked without crutches.The treatment of malignant bone tumors around the knee joint with 3D printed osteotomy guide plate and personalized prosthesis can preserve the articular surface, obtain good limb function, reduce the risk of aseptic loosening of prosthesis, and achieve better mid-term effectiveness.探讨在膝关节周围恶性骨肿瘤患者中使用3D打印截骨导板与个性化假体进行保膝治疗的中期疗效。.回顾分析2016年9月—2018年10月采用3D打印截骨导板与个性化假体进行保留关节面的肿瘤切除重建术治疗的12例膝关节周围恶性肿瘤患者临床资料。其中男7例，女5例；发病年龄7～59岁，中位年龄44.5岁。骨肉瘤11例、纤维肉瘤1例，均为Enneking ⅡB期。肿瘤与关节面距离为5.5～8.2 cm，平均6.94 cm。术后观察患者切口愈合、肿瘤复发、有无假体周围骨折及无菌性松动等情况，使用美国肌肉骨骼肿瘤学会（MSTS）评分进行功能评价，并测定膝关节屈曲活动度。.12例患者均获随访，随访时间41～66个月，平均54.5个月。截骨长度为14～26 cm，平均22.08 cm。除2例患者出现切口浅表感染，未发生累及假体的深部感染，无患者因假体感染行翻修手术。随访期间2例发生局部复发，3例发生远处转移，患者总无病生存率为58.3%。2例患者因肺转移死亡，患者总生存率为83.3%。1例患者因局部复发截肢，1例假体断裂行人工全膝关节置换术翻修；随访期间未发生假体无菌性松动及假体周围骨折，总假体生存率为83.3%。末次随访时10例患者获得了满意膝关节屈曲活动度，达95°～125°，平均110°；2例患儿因疼痛无法配合早期康复治疗，膝关节屈曲活动度恢复不理想，分别为50° 和75°。所有患者均获得了可接受的下肢功能，MSTS评分为26～30分，平均28分；患者均可不拄拐独立行走。.3D打印截骨导板与个性化假体治疗膝关节周围恶性骨肿瘤，可以保留关节面，患者可获得良好肢体功能，减少假体无菌性松动风险，中期疗效较好。.

Purpose To investigate the indications, approaches, resection methods, and complications of total sacrectomy with a combined antero-posterior approach for malignant sacral tumours. Methods Fourteen cases of primary malignant sacral tumours treated with total sacrectomy between January 2012 and 2018 were retrospectively analysed. All patients presented with pre-operative lumbosacral pain or constipation. A combined antero-posterior approach was used for tumour resection, and the spinal pedicle screw rod system was used to achieve ilio-lumbar stability. The visual analogue scale (VAS) and Musculoskeletal Tumor Society (MSTS) scores were used to assess pain and lower limb function, respectively. The mean operative time and intra-operative blood loss were 6.54 hours and 2935 mL, respectively. The mean follow-up period was 62 months. Results None of the patients died peri-operatively. At the last follow-up, ten patients were continuously disease-free, three were alive with disease, and one died of disease from lung metastasis. Tumour recurrence occurred in three patients. The MSTS scores ranged from 6 to 28 (20.00–93.33%, 6/30–28/30) with an average of 20 (66.67%, 20/30). Seven patients could walk independently in public, five could only walk at home using a walking aid, and two could only lie down and stand for a short time. Thirteen patients developed post-operative complications such as skin necrosis, screw loosening, connecting rod fracture, neuropathic pain, sciatic nerve injury, dysuria, and urinary incontinence. Conclusion Total sacrectomy can effectively treat malignant sacral tumours with good resection boundaries and prognosis. However, the high incidence of post-operative complications may impact post-operative neurological function.

As a DNA receptor in the cytoplasm, cyclic GMP-AMP synthase (cGAS) contributes to the recognition of abnormal DNA in the cytoplasm and contributes to the stimulator of interferon genes (STING) signaling pathway. cGAS could mediate the expression of interferon-related genes, inflammatory-related factors, and downstream chemokines, thus initiating the immune response. The STING protein is a key effector downstream of the DNA receptor pathway. It is widely expressed across cell types such as immune cells, tumor cells, and stromal cells and plays a role in signal transduction for cytoplasmic DNA sensing and immunity. STING agonists, as novel agonists, are used in preclinical research and in the treatment of various tumors via clinical trials and have displayed attractive application prospects. Studying the cGAS-STING signaling pathway will deepen our understanding of tumor immunity and provide a basis for the research and development of antitumor drugs.

We present a rare case of a primary intradural extramedullary Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) in the thoracolumbar spine and review the current literature. We describe the imaging manifestations, pathological features, surgical methods, and patient survival to shed light on the clinical management of this rare tumor. A 32-year-old man experienced progressive low back pain for more than 1 month. An intradural extramedullary tumor from T12 to L2 was detected on magnetic resonance imaging. He underwent a thoracolumbar laminotomy for decompression, complete excision of the intradural extramedullary tumor, and internal fixation with pedicle screws. A histopathological examination confirmed that the tumor was a PIEES/PNET via an immunohistochemical study of the surgically resected tissues. Postoperatively, the patient received chemotherapy and radiotherapy. No recurrence, metastasis, or failure of internal fixation were noted at a 17-month post-surgery radiographic examination. PIEES/PNET of the thoracolumbar spine is extremely rare. Treatment is difficult because the current literature is sparse and cases are rare. Complete resection combined with chemotherapy and radiotherapy effectively reduces recurrence and metastasis.

Osteosarcoma is a highly invasive kind of malignant bone tumor. Exosomes are a type of extracellular vesicles that play an important role in intercellular communication in the microenvironment. Tumor cell progression is promoted through the interaction between exosomes and cells in the microenvironment (including immune cells, mesenchymal cells, and endothelial cells) during tumor development. Neoplastic exosomes can carry a variety of biological information molecules, such as proteins, lipids, and nucleic acids. These molecules play an important clinical role, not only being able domesticate the recipient cells but also being recognized as tumor specific markers. At the same time, exosomes secreted by osteosarcoma can also cooperate with antigen-presenting cells to activate the body's immune response and then to exert anti-tumor effects. Studies on exosomes may be a breakthrough in the search for a new osteosarcoma treatment. In this study, we review the role of neoplastic exosomes in the osteosarcoma microenvironment, summarize their potential as tumor markers, and investigate their clinical application prospects.

The current global burden of tuberculosis (TB) is one of the greatest challenges to public health, particularly in developing countries, and thus effective diagnostic methods and treatment options for TB remain a central topic in basic and clinical research. Heparin-binding hemagglutinin (HBHA)-specific immune responses have been linked to protection against TB. The binding of HBHA-coated beads to epithelial and endothelial cell layers may trigger transcytosis of the beads, which is the basis for extrapulmonary dissemination. In addition, HBHA has been confirmed as a potential diagnostic marker for TB, and it is important in developing new TB vaccines and anti-TB drugs. Recently, basic research on HBHA has been intensified. The HBHA application in the field of prevention and treatment should be further explored. In addition, the existing research achievements have shown its broad application prospects. Currently, there are no relevant specialized products, and research should be accelerated. These products may contribute to the application of HBHA in the diagnosis, prevention and treatment of TB.

Human sulfatase‑1 (HSulf‑1) is emerging as a novel prognostic biomarker in breast cancer. Previous studies demonstrated HSulf‑1 to function as a negative regulator of cyclin D1 in breast cancer. Accumulating preclinical evidence is supporting the efficacy of cyclin‑dependent kinase (CDK) 4/6 inhibitors against the luminal androgen receptor sub‑type of triple‑negative breast cancer (TNBC). It was therefore hypothesized that HSulf‑1 may cooperate with CDK4/6 inhibitors to control cell cycle progression in breast cancer cells. HSulf‑1 expression was found to be downregulated in TNBC tissues and cell lines compared with that in healthy tissues and non‑breast cancer cell lines, respectively. High levels of HSulf‑1 expression was also found to be associated with increased progression‑free survival and overall survival in patients with TNBC. Functionally, it was demonstrated that HSulf‑1 served as tumor suppressor in TNBC by inducing cell cycle arrest and apoptosis whilst inhibiting proliferation, epithelial‑mesenchymal transition, migration and invasion. Subsequent overexpression of HSulf‑1 coupled with treatment with the CDK4/6 inhibitor palbociclib exhibited a synergistic antitumor effect on retinoblastoma (RB)‑positive TNBC. Further studies revealed the mechanism underlying this cooperative antiproliferative effect involved to be due to the prohibitive effects of HSulf‑1 on the palbociclib‑induced accumulation of cyclin D1 through AKT/STAT3 and ERK1/2/STAT3 signaling. Taken together, findings from the present study not only suggest that HSulf‑1 may be a potential therapeutic target for TNBC, but also indicate that combinatorial treatment could be an alternative therapeutic option for RB‑positive TNBC, which may open novel perspectives.

Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor efficacy of PDT is limited due to the hypoxic microenvironment of tumor. In this study, classic PDT agent indocyanine green (ICG) and hypoxia-activated chemotherapeutic drug tirapazamine (TPZ) were loaded on mesoporous polydopamine (PDA) to construct PDA@ICG-TPZ nanoparticles (PIT). Then, PIT was camouflaged with cyclic arginine-glycine-aspartate (cRGD) modified tumor cell membranes to obtain the engineered membrane-coated nanoreactor (cRGD-mPIT). The nanoreactor cRGD-mPIT could achieve the dual-targeting ability via tumor cell membrane mediated homologous targeting and cRGD mediated active targeting. With the enhanced tumor-targeting and penetrating delivery system, PIT could efficiently accumulate in hypoxic tumor cells and the loaded drugs were quickly released in response to near-infrared (NIR) laser. The nanoreactor might produce cytotoxic ROS under NIR and further enhance hypoxia within tumor to activate TPZ, which efficiently inhibited hypoxic tumor by synergistic photodynamic-chemotherapy. Mechanically, hypoxia-inhibitory factor-1α (HIF-1α) was down-regulated by the synergistic therapy. Accordingly, the cRGD-mPIT nanoreactor with sustainable and cascade anti-tumor effects and satisfied biosafety might be a promising strategy in hypoxic tumor therapy.

The epithelial-to-mesenchymal transition (EMT) is a reversible process that may interact with tumor immunity through multiple approaches. Increasing evidence has demonstrated the interconnections among EMT-related processes, tumor microenvironment, immune activity, as well as the potential influence on immunotherapy response. Long non-coding RNAs (lncRNAs) are emerging as critical modulators of gene expression. They can play fundamental roles in tumor immunity and act as promising biomarkers of immunotherapy response. However, the potential roles of lncRNA in the crosstalk of EMT and tumor immunity are still unclear in sarcoma. We obtained multi-omics profiling of 1440 pan-sarcoma patients from 19 datasets. Through an unsupervised consensus clustering approach, we categorized EMT molecular subtypes. We subsequently identified 26 EMT molecular subtype and tumor immune-related lncRNAs (EILncRNA) across pan-sarcoma types and developed an EILncRNA signature-based weighted scoring model (EILncSig). The EILncSig presented a favorable performance in predicting the prognosis of sarcoma, and the high-EILncSig was associated with exclusive TME characteristics with desert-like infiltration of immune cells. Multiple altered pathways, somatically mutated genes and recurrent CNV regions associated with EILncSig were identified. Notably, the EILncSig was associated with the efficacy of immune checkpoint inhibition (ICI) therapy. We additionally screened compounds such as Irinotecan that may have the potential to convert the EILncSig phenotype. By integrative analysis on multi-omics profiling, our findings provide a comprehensive resource for understanding the functional role of lncRNA-mediated immune regulation in sarcomas, which may advance the understanding of tumor immune response and the development of lncRNA-based immunotherapeutic strategies for sarcoma.

Reconstruction after resection has always been an urgent problem in the treatment of bone tumours. There are many methods that can be used to reconstruct bone defects; however, there are also many complications, and it is difficult to develop a safe and effective reconstruction plan for the treatment of bone tumours. With the rapid development of digital orthopaedics, three-dimensional printing technology can solve this problem. The three-dimensional printing of personalised prostheses has many advantages. It can be used to print complex structures that are difficult to fabricate using traditional processes and overcome the problems of stress shielding and low biological activity of conventional prostheses. In this study, 12 patients with bone tumours were selected as research subjects, and based on individualised reverse-engineering design technology, a three-dimensional model of each prosthesis was designed and installed using medical image data. Ti6Al4V was used as the raw material to prepare the prostheses, which were used to repair bone defects after surgical resection. The operation time was 266.43 ± 21.08 minutes (range 180-390 minutes), and intraoperative blood loss was 857.26 ± 84.28 mL (range 800-2500 mL). One patient had delayed wound healing after surgery, but all patients survived without local tumour recurrence, and no tumour metastasis was found. No aseptic loosening or structural fracture of the prosthesis, and no non-mechanical prosthesis failure caused by infection, tumour recurrence, or progression was observed. The Musculo-Skeletal Tumour Society (MSTS) score of limb function was 22.53 ± 2.09 (range 16-26), and ten of the 12 patients scored ≥ 20 and were able to function normally. The results showed that three-dimensional printed prostheses with an individualised design can achieve satisfactory short-term clinical efficacy in the reconstruction of large bone defects after bone tumour resection.

Circular RNA (circRNA) is important in the pathogenesis of many diseases. By analyzing the GSE96964 microarray, hsa_circ_0000285 (circ-0000285) was found to be highly expressed in osteosarcoma. Recent studies have shown that circ-0000285 is capable of regulating proliferative and migratory potentials. Here, we investigated the potential functions in regulating osteosarcoma cells to proliferate and migrate. First of all, qRT-PCR data revealed a higher level of circ-0000285 in osteosarcoma cell lines relative to normal osteoblasts. Through dual-luciferase reporter gene assay and RIP assay, we confirmed that both circ-0000285 and TGFB2 could directly bind to miRNA-599. Regulatory effects of circ-0000285 and miRNA-599 on proliferative and migratory potentials were evaluated by EdU assay and transwell migration assay. It is indicated that circ-0000285 overexpression enhanced the proliferative and migratory potentials of osteosarcoma, which could be reversed by miRNA-599 overexpression. This study revealed a vital role of circ-0000285/miRNA-599/TGFB2 axis in regulating the progression of osteosarcoma, providing a novel perspective for clarifying its pathogenesis.

Compared to other diseases, early or atypical spinal tuberculosis (TB) is prone to being misdiagnosed due to the lack of specific clinical manifestations and misleading negative results of various laboratory analyses and imaging examinations. Various methods for diagnosing spinal TB have become research hotspots. Recently, it has been proposed that effective vaccination is a mainstay of long-term policies to combat and control the TB epidemic. However, some new TB vaccines require further evaluation and clinical trials to demonstrate their efficiency and safety. Thus, early diagnosis and effective treatment are the other essential long-term strategies for controlling the TB epidemic immunization is closely associated with the diagnosis of spinal TB, which will become the focus of future research and set the direction for future developments. The present study provides a case series and a literature review of the characteristics of spinal TB to provide guidance for the diagnosis, treatment and prognosis of spinal TB.

BackgroundSacroiliac joint tumor is rare, and the reconstruction after tumor resection is difficult. We aimed to analyze and compare the clinical effects of three-dimensional (3D) printed prostheses and bone cement combined with screws for bone defect reconstruction after sacroiliac joint tumor resection.MethodsTwelve patients with sacroiliac joint tumors who underwent tumor resection and received 3D-printed prostheses to reconstruct bone defects in our hospital from January 2014 to December 2020 were included in the study group Twelve matched patients who underwent sacroiliac joint tumor resection and reconstruction with bone cement and screws in the same time period were selected as the control group.ResultsIn the 3D-printing group, six cases were extensively excised, and six cases were marginally excised. All patients were followed up for 6–90 months, and the median follow-up time was 21 months. Among them, nine patients had disease-free survival, two survived with tumor recurrence, and one died due to tumor metastasis. The MSTS-93 score of the surviving patients was 24.1 ± 2.8. The operation time was 120.30 ± 14.50 min, and the intraoperative bleeding was 625.50 ± 30.00 ml. In the control group, seven cases were extensively excised, and five cases were marginally excised. All patients were followed up for 6–90 months, with a median follow-up time of 20 months. Among them, nine patients had disease-free survival, one survived with tumor recurrence, and two died due to tumor metastasis. The MSTS-93 score of the patients was 18.9 ± 2.6. The operation time was 165.25 ± 15.00 min, and the intraoperative bleeding was 635.45 ± 32.00 ml. There was no significant difference in survival status, intraoperative blood loss, or complications between the two groups (P>0.05). However, there were statistically significant differences in operative time and postoperative MSTS-93 scores between the two groups (PConclusionsAfter resection of the sacroiliac joint tumor, reconstruction using 3D printed prostheses was shorter and resulted in better movement function.

Low back pain is a vital musculoskeletal disease that impairs life quality, leads to disability and imposes heavy economic burden on the society, while it is greatly attributed to intervertebral disc degeneration (IDD). However, the existing treatments, such as medicines, chiropractic adjustments and surgery, cannot achieve ideal disc regeneration. Therefore, advanced bioactive therapies are implemented, including stem cells delivery, bioreagents administration, and implantation of biomaterials etc. Among these researches, few reported unsatisfying regenerative outcomes. However, these advanced therapies have barely achieved successful clinical translation. The main reason for the inconsistency between satisfying preclinical results and poor clinical translation may largely rely on the animal models that cannot actually simulate the human disc degeneration. The inappropriate animal model also leads to difficulties in comparing the efficacies among biomaterials in different reaches. Therefore, animal models that better simulate the clinical charateristics of human IDD should be acknowledged. In addition, in vivo regenerative outcomes should be carefully evaluated to obtain robust results. Nevertheless, many researches neglect certain critical characteristics, such as adhesive properties for biomaterials blocking annulus fibrosus defects and hyperalgesia that is closely related to the clinical manifestations, e.g., low back pain. Herein, in this review, we summarized the animal models established for IDD, and highlighted the proper models and parameters that may result in acknowledged IDD models. Then, we discussed the existing biomaterials for disc regeneration and the characteristics that should be considered for regenerating different parts of discs. Finally, well-established assays and parameters for in vivo disc regeneration are explored.

Osteosarcoma (OS) is a malignant solid tumor prone to lung metastasis that occurs in adolescents aged 15-19 years. Neoadjuvant chemotherapy and surgical treatment aimed at curing OS have gained limited progress over the last 30 years. Exploring new effective second-line therapies for OS patients is a serious challenge for researchers. Quercetin, a multiple biologically active polyphenolic flavonoid, has been used in tumor therapy. However, the exact mechanism of quercetin is still unknown, which limits the application of quercetin. In the current study, we found that quercetin could inhibit JAK2 through the JH2 domain in a non-covalent manner, resulting in the inhibition of OS proliferation and immune escape via the JAK2-STAT3-PD-L1 signaling axis. More importantly, to overcome the shortcomings of quercetin, including low water solubility and low oral availability, we encapsulated it with folic acid-modified liposomes. The transportation of quercetin by folic acid-modified liposomes may provide a feasible strategy to cure OS.

Due to the rarity and heterogeneity, it is challenging to explore and develop new therapeutic targets for patients with sarcoma. Recently, immune cell infiltration in the tumor microenvironment (TME) was widely studied, which provided a novel potential approach for cancer treatment. The competing endogenous RNA (ceRNA) regulatory network has been reported as a critical molecular mechanism of tumor development. However, the role of the ceRNA regulatory network in the TME of sarcoma remains unclear. In this study, gene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) sarcoma datasets, and an immune infiltration-related ceRNA network was constructed, which comprised 14 lncRNAs, 13 miRNAs, and 23 mRNAs. Afterward, we constructed an immune infiltration-related risk score model based on the expression of IRF1, MFNG, hsa-miR-940, and hsa-miR-378a-5p, presenting a promising performance in predicting the prognosis of patients with sarcoma.

Programmed necrosis of nucleus pulposus (NP) cells caused by excessive compression is a crucial factor in the etiopathogenesis of intervertebral disc degeneration (IVDD). The endoplasmic reticulum (ER) and mitochondria are crucial regulators of the cell death signaling pathway, and their involvement in IVDD has been reported. However, the specific role of ER stress (ERS) and ER-mitochondria interaction in compression-induced programmed necrosis of NP cells remains unknown. Our studies revealed that compression enhanced ERS and the association between ER and mitochondria in NP cells. Suppression of ERS via 4-phenylbutyrate (4-PBA) or ER-mitochondrial Ca2+ crosstalk by inhibiting the inositol 1,4,5-trisphosphate receptor, glucose-regulated protein 75, voltage-dependent anion-selective channel 1 complex (IP3R–GRP75–VDAC1 complex) protected NP cells against programmed necrosis related to the poly(ADP-ribose) polymerase (PARP) apoptosis-inducing factor (AIF) pathway. Moreover, excessive reactive oxygen species are critical activators of ERS, leading to mitochondrial Ca2+ accumulation and consequent programmed necrosis. These data indicate that ERS and ER-mitochondrial Ca2+ crosstalk may be potential therapeutic targets for the treatment of IVDD-associated disorders. These findings provide new insights into the molecular mechanisms underlying IVDD and may provide novel therapeutic targets.

Programmed necrosis of nucleus pulposus (NP) cells caused by excessive compression is a crucial factor in the etiopathogenesis of intervertebral disc degeneration (IVDD). The endoplasmic reticulum (ER) and mitochondria are crucial regulators of the cell death signaling pathway, and their involvement in IVDD has been reported. However, the specific role of ER stress (ERS) and ER-mitochondria interaction in compression-induced programmed necrosis of NP cells remains unknown. Our studies revealed that compression enhanced ERS and the association between ER and mitochondria in NP cells. Suppression of ERS via 4-phenylbutyrate (4-PBA) or ER-mitochondrial Ca2+ crosstalk by inhibiting the inositol 1,4,5-trisphosphate receptor, glucose-regulated protein 75, voltage-dependent anion-selective channel 1 complex (IP3R–GRP75–VDAC1 complex) protected NP cells against programmed necrosis related to the poly(ADP-ribose) polymerase (PARP) apoptosis-inducing factor (AIF) pathway. Moreover, excessive reactive oxygen species are critical activators of ERS, leading to mitochondrial Ca2+ accumulation and consequent programmed necrosis. These data indicate that ERS and ER-mitochondrial Ca2+ crosstalk may be potential therapeutic targets for the treatment of IVDD-associated disorders. These findings provide new insights into the molecular mechanisms underlying IVDD and may provide novel therapeutic targets.

The development of tissue engineering has led to new strategies for mitigating clinical problems; however, the design of the tissue engineering materials remains a challenge. The limited sources and inadequate function, potential risk of microbial or pathogen contamination, and high cost of cell expansion impair the efficacy and limit the application of exogenous cells in tissue engineering. However, endogenous cells in native tissues have been reported to be capable of spontaneous repair of the damaged tissue. These cells exhibit remarkable plasticity, and thus can differentiate or be reprogrammed to alter their phenotype and function after stimulation. After a comprehensive review, we found that the plasticity of these cells plays a major role in establishing the cell source in the mechanism involved in tissue regeneration. Tissue engineering materials that focus on assisting and promoting the natural self-repair function of endogenous cells may break through the limitations of exogenous seed cells and further expand the applications of tissue engineering materials in tissue repair. This review discusses the effects of endogenous cells, especially stem cells, on injured tissue repairing, and highlights the potential utilisation of endogenous repair in orthopaedic biomaterial constructions for bone, cartilage, and intervertebral disc regeneration.

Osteoarticular tuberculosis, a chronic inflammatory disease characterized by Mycobacterium tuberculosis (M.tb) infection, has become a serious problem in China. The present study was conducted to determine the mechanism of action of tumor necrosis factor (TNF)-α in the pathogenesis of osteoarticular tuberculosis. The number of osteoclasts in osteoarticular tuberculosis tissue samples was detected by tartrate-resistant acid phosphatase staining. Autophagy and apoptosis of osteoclasts were detected by western blotting, reverse transcription-quantitative PCR, transmission electron microscopy and TUNEL staining. The results showed that autophagy and the number of osteoclasts increased in the lesions of patients with osteoarticular tuberculosis compared with osteoarthritis samples. Moreover, activation of osteoclast autophagy inhibited the apoptosis of osteoclasts infected with M.tb, and increased the expression level of TNF-α. The results showed that TNF-α enhanced the autophagic activity of M.tb-infected osteoclasts and inhibited cell apoptosis. These findings indicated that M.tb infection induced osteoclast production and inhibited osteoclast apoptosis by regulating TNF-α-mediated osteoclast autophagy, revealing a new mechanism for TNF-α in the pathogenesis of osteoarticular tuberculosis.

Small nucleolar RNA host gene 6 (SNHG6) is a newly discovered long non-coding RNA (lncRNA), while the regulatory mechanism of SNHG6 in chondrosarcoma is largely unknown. Here we found that SNHG6 expression was upregulated and showed positive correlation with the progression of chondrosarcoma. Functional assays demonstrated that SNHG6 was required for the proliferation, migration, and invasion of chondrosarcoma cells. Mechanistic study revealed that SNHG6 could recruit EZH2 and maintain high level of H3K27me3 to repress the transcription of tumor-suppressor genes, including KLF6. KLF6 was found to bind to the promoter region of SP1 and restrained its transcription, while SP1 could be recruited to the promoter region of SNHG6 and promoted its transcription to form a positive loop. In summary, this study reveals that SP1-induced SNHG6 forms a positive loop to facilitate the carcinogenesis of chondrosarcoma through the suppression of KLF6 by recruiting EZH2, which manifests the oncogenic function of SNHG6 in chondrosarcoma.

// Jian-Xiang Liu 1 , Zhi-Cai Zhang 1 , Zeng-Wu Shao 1 , Fei-Fei Pu 1 , Bai-Chuan Wang 1 , Yu-Kun Zhang 1 , Xian-Lin Zeng 1 , Xiao-Dong Guo 1 , Shu-Hua Yang 1 and Tong-Chuan He 2 1 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 2 Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago 60637, IL, USA Correspondence to: Jian-Xiang Liu, email: ljx4573@yeah.net Keywords: circulating tumor cells (CTCs), giant cell tumor of bone (GCT), TRAIL-R1 Received: March 12, 2017 Accepted: March 29, 2017 Published: April 11, 2017 ABSTRACT Giant cell tumor of bone (GCT), which frequently occurs in the patients’ spine, is relatively prevalent in Chinese population. A group of GCT invades into vessels and appears to be circulating tumor cells (CTCs) responsible for the distal metastasis of the primary tumor. So far the cell surface markers of GCT have not been determined. In the current study, we aimed to identify a novel CTC marker with higher specificity in GCT. TRAIL-R1+ cells were purified from GCT cell lines. The TRAIL-R1+ cells were compared with total GCT cells for tumor sphere formation, chemo-resistance, tumor formation in nude mice, and frequency of developing distal metastases. We found that TRAIL-R1+ GCT cells appeared to be highly enriched for CTCs in GCT. Compared to total GCT cells, TRAIL-R1+ GCT cells generated significantly more tumor spheres in culture, were higher chemo-resistant, and had a higher frequency of being detected in the circulation after subcutaneous transplantation as well as development of distal metastases. Thus, we conclude that TRAIL-R1+ may be a novel CTC marker in GCT. Selective elimination of TRAIL-R1+ GCT cells may improve the current GCT therapy.

Triple-negative breast cancer (TNBC), which represents 15%-20% of all breast cancers, is defined by the absence of estrogen receptor (ER) and progesterone receptor (PR) and overexpression of human epidermal growth factor receptor 2 (HER2). Owing to the absence of specific therapeutic targets and its aggressive biologic characteristics, TNBC patients often experience a high risk of disease progression and poor overall survival. Furthermore, TNBC exhibits an early pattern of recurrence with a peak recurrence risk at 2-3 years after surgery. Currently, chemotherapy continues to be the mainstay in TNBC patients; however, such treatment leaves them associated with a high rate of local and systemic relapses even in early-stage (T1-2N0-1M0). Therefore, in early-stage disease, greater emphasis is placed on locoregional treatments, based on radiation therapy (RT) after surgery, to reduce local and systemic relapses. However, there are no specific treatment guidelines for early-stage (T1-2N0-1M0) TNBC patients. In this review, we discuss the type of surgery received and the relevant adverse clinicopathologic factors and underlying BRCA1 mutation status regarding the influence of tailing postmastectomy radiotherapy (PMRT). In addition, we assess the role of PMRT in early-stage (T1-2N0-1M0) TNBC patients.

T-cell immunoglobulin and mucin domain-containing-3 (TIM-3) performs a critical function in immune tolerance by suppressing the activation and proliferation of T cells. TIM-3 serves an important role in tumor progression in a number of carcinomas, including non-small cell lung cancer, hepatitis B virus-associated hepatocellular carcinoma, Langerhans cell sarcoma, head and neck cancer and follicular B cell non-Hodgkin lymphoma. The aim of the present study was to evaluate the possible association of TIM-3 with the prognosis of osteosarcoma. TIM-3 expression was assessed by immunohistochemical analysis in osteosarcoma tissues. The association between TIM-3 expression and prognosis was examined. To assess the association between TIM-3 expression levels and clinicopathological features, a Fisher's exact test was used. TIM-3 overexpression was indicated to be associated with surgical treatment and survival. Kaplan-Meier analysis indicated that TIM-3 is an independent predictor of overall survival, and its overexpression was indicated to be associated with poor prognosis in patients with osteosarcoma. Additionally, reverse transcription-quantitative polymerase chain reaction and western blot analysis were carried out to evaluate TIM-3 expression levels in fresh tumor tissue samples, adjacent-tissue samples, osteosarcoma cell lines, and in an osteoblastic cell line. TIM-3 was indicated to be overexpressed in fresh osteosarcoma tissue samples and in osteosarcoma cell lines. In conclusion, TIM-3 overexpression is associated with poor survival among patients with osteosarcoma and may be a possible therapeutic target in these types of tumors.

Breast cancer is a highly heterogeneous disease consisting of five disease subtypes with distinct histological characteristics, clinical behaviors and prognostic features. Stanniocalcin-1 (STC1) is a secreted glycoprotein hormone that has been demonstrated to regulate calcium and phosphate homeostasis. Mammalian STC1 is expressed in various tissues and is implicated in multiple physiological and pathophysiological processes. In addition, growing evidence has suggested that STC1 serves an oncogenic role in a number of different types of tumor. However, the role of STC1 in breast cancer is complex, considering that some studies have shown that it exerts an oncogenic role, whereas other studies have demonstrated the opposite. The aim of the present review article is to evaluate the currently available data on mammalian STC1 and discuss its potential roles in each subtype of breast cancer.

MicroRNAs are a group of small non-coding RNAs that play a complex role in post-transcriptional gene expression and can be used for diagnosis, prognosis, and targeted treatment. Despite advances in diagnosis and treatment of chondrosarcoma, its underpinning molecular mechanisms still remain elusive. Given the recent increasing knowledge base of micro RNA (miRNA) roles in neoplasia, both as oncogenes and tumor suppressor genes, this review will focus on discussing the available data on expression profiles and potential roles of miRNA in chondrosarcoma. Accumulating evidence suggests that microRNAs have the potential to be used in the future for clinical management of chondrosarcoma.

The aim of the present study was to investigate the feasibility of da Vinci robotic surgery in the treatment of presacral tumors, and to observe its efficacy and safety. Between March 2016 and April 2019, 12 patients with presacral nerve sheath tumors underwent da Vinci robotic surgery, and the integrity of the tumor resection, surgical duration, pre- and postoperative visual analog scale (VAS) score, intra- and postoperative blood losses, postoperative bedtime, hospital stay and complications were observed. The tumor was completely removed in all 12 patients, the surgical duration ranged between 76 and 245 min (mean, 106.08 min) and the intraoperative blood loss was 76–145 ml (mean, 101.67 ml). The average preoperative VAS score of the patients was 3.25, and the average VAS score at 1 week, 1 month and 3 months post operation were 1.08, 0.42 and 0.08, respectively. All patients were out of bed on the second day after surgery, and the postoperative drainage was 10–50 ml (mean, 33.50 ml). The patients were hospitalized for 3–5 days (mean, 3.92 days). No complications occurred peri- or postoperatively, and wound pain was the main source of postoperative discomfort. In conclusion, the da Vinci robot can be applied to presacral nerve sheath tumors with high surgical safety, low-level bleeding, a rapid recovery and a short hospital stay, making it worthy of further study.

Breast cancer is a highly heterogeneous disease consisting of five disease subtypes with distinct histological characteristics, clinical behaviors and prognostic features. Stanniocalcin-1 (STC1) is a secreted glycoprotein hormone that has been demonstrated to regulate calcium and phosphate homeostasis. Mammalian STC1 is expressed in various tissues and is implicated in multiple physiological and pathophysiological processes. In addition, growing evidence has suggested that STC1 serves an oncogenic role in a number of different types of tumor. However, the role of STC1 in breast cancer is complex, considering that some studies have shown that it exerts an oncogenic role, whereas other studies have demonstrated the opposite. The aim of the present review article is to evaluate the currently available data on mammalian STC1 and discuss its potential roles in each subtype of breast cancer.

Background and aim To explore the diagnostic value of recombinant heparin-binding hemagglutinin adhesin (HBHA) protein antigen in spinal tuberculosis. Materials and methods Forty patients with spinal tuberculosis were included in the experimental group and 40 healthy people were included in the control group. Serum IgG antibody expression level was detected with recombinant HBHA protein as the antigen, using enzyme-linked immunosorbent assay (ELISA) detection. Results Patients with spinal tuberculosis and healthy volunteers were included in this study. A total of 40 eligible patients with spinal tuberculosis were included (24 males and 16 females, aged 18-72 years, with an average age of 41.24 ± 15.74 years). Forty healthy people were included (21 males and 19 females, aged 18-70 years, with an average age of 41.33 ± 12.36 years). On comparing the groups, no significant difference was found in the general data (P >0.05). IgG antibody level in the experimental group was higher than that in the control group, and the difference was significant (P < 0.00001). Conclusions Detection of serum HBHA protein antibody is of great value in the auxiliary diagnosis of spinal tuberculosis, and high HBHA expression can be used as an indicator for diagnosis of spinal tuberculosis.

Aim: To compare efficacy and safety of anticoagulants apixaban and rivaroxaban after lumbar spine surgery retrospectively. Methods: In this study comprising 480 patients, lower-limb swelling, deep venous thrombosis, pulmonary embolism, blood loss, ecchymosis and D-dimer changes were observed. Results: The changes in perimeter of the legs were tested, and significant differences were noted 10 cm above the patella, but no significant differences 10 cm below the patella. Twelve thrombotic events occurred in the apixaban group and nine in rivaroxaban group. No significant difference in the incidences of thromboembolic events (p = 1.00). Compared with rivaroxaban, there was significantly less bleeding in the apixaban group (p = 0.03). Conclusion: Apixaban and rivaroxaban were equally effective anticoagulation therapies that exhibited similar preventive effects against postoperative venous thromboembolism after lumbar spine surgery., Lay abstract Venous thromboembolism (VTE) can lead to severe morbidity with poor quality of life and even sudden death related to pulmonary embolism. VTE risk factors are common in patients with degenerative spine, and without prophylaxis, approximately 15% of patients undergoing posterior spinal surgery develop deep vein thrombosis. In this study, efficacy and safety of anticoagulants apixaban and rivaroxaban after lumbar spine surgery were compared retrospectively. This study confirmed that apixaban and rivaroxaban were equally effective anticoagulation therapies that exhibited similar preventive effects against postoperative VTE after lumbar spine surgery.

MTH1 has become a new rising star in the field of 'cancer phenotypic lethality' and can be targeted in many kinds of tumors. This study aimed to explore the anticancer effect of MTH1-targeted drug (S)-crizotinib on osteosarcoma (OS) cells. We detected MTH1 expression in OS tissues and cells using immunohistochemistry and western blot. The effects of MTH1 on OS cell viability were explored using the siRNA technique and CCK8. The anticancer effects of the MTH1-targeted drug (S)-crizotinib on OS cells were explored by in-vitro assays. The intracellular 8-oxo-dGTP level and oxygen reactive species (ROS) of OS cells were detected by Cy3-conjugated avidin staining and dichlorofluorescein diacetate staining, respectively. The expression of MTH1 was significantly higher in OS tissues and cell lines than that in the corresponding adjacent tissues and osteoblastic cell line. The proliferation of OS cells was significantly inhibited through knockdown of MTH1 by siRNA technology. (S)-Crizotinib could inhibit the proliferation of OS cells with an increase in the apoptosis levels and causing G0/G1 arrest by targeting MTH1 and activating ROS. In addition, (S)-crizotinib could inhibit the migration of OS cells. (S)-Crizotinib could suppress the proliferation and migration, cause G0/G1 arrest, and increase the apoptosis level of OS cells by targeting MTH1 and activating ROS. This study will provide a promising therapeutic target and the theoretical basis for the clinical application of (S)-crizotinib in OS.