The Dilemma of Balance between Benefits and Losses for Chondromyxoid Fibroma-like Osteosarcoma in Thoracic Spine with Azygos Tumor Thrombosis: A Case Report.

Background: Chondromyxoid fibroma-like osteosarcoma (CMF-OS) is an extremely rare subtype of osteosarcoma, its clinical data are scarce, and our understanding of it is far from sufficient. As it has few typical imaging manifestations, it is not uncommonly misdiagnosed clinically. Azygos vein thrombosis is also a rare entity, and there is a big controversy over treatments for it. Case presentation: Herein, we report a case of CMF-OS that occurred in the spine, coincidently, azygos vein thrombosis was found. A young male patient came to our clinic because of continuous back pain, and a neoplastic lesion was suspected in the thoracolumbar vertebrae. The pathological results of the biopsy showed a low grade of osteosarcoma, and chondromyxoid fibroma-like osteosarcoma was the primary diagnosis. Since the tumor cannot be en-bloc resected, he received palliative decompression surgery, followed by radio and chemotherapy. Azygos vein tumor thrombosis was not treated and, unfortunately, he died of heart failure caused by the thrombus migrating from the azygos vein to the right atrium. Before the palliative decompression surgery, both the patient and the clinical team were trapped in the dilemma of how big a surgery should be carried out to maximize the benefits of this patient. Results and complications: CMF-OS is indeed more aggressive than its pathological sections suggest. Guidelines for osteosarcoma should be followed. Furthermore, it is important to recognize the danger of tumor thrombosis in the azygos vein. Preventive measures have to be performed in a timely manner to avoid catastrophic results.

The nanoformula of zoledronic acid and calcium carbonate targets osteoclasts and reverses osteoporosis.

Osteoporosis is known as an imbalance in bone catabolism and anabolism. Overactive bone resorption causes bone mass loss and increased incidence of fragility fractures. Antiresorptive drugs are widely used for osteoporosis treatment, and their inhibitory effects on osteoclasts (OCs) have been well established. However, due to the lack of selectivity, their off-target and side effects often bring suffering to patients. Herein, an OCs' microenvironment-responsive nanoplatform HA-MC/CaCO3/ZOL@PBAE-SA (HMCZP) is developed, consisting of succinic anhydride (SA)-modified poly(ß-amino ester) (PBAE) micelle, calcium carbonate shell, minocycline-modified hyaluronic acid (HA-MC) and zoledronic acid (ZOL). Results indicate that HMCZP, as compared with the first-line therapy, could more effectively inhibit the activity of mature OCs and significantly reverse the systemic bone mass loss in ovariectomized mice. In addition, the OCs-targeted capacity of HMCZP makes it therapeutically efficient at sites of severe bone mass loss and allows it to reduce the adverse effects of ZOL, such as acute phase reaction. High-throughput RNA sequencing (RNA-seq) reveals that HMCZP could down-regulate a critical osteoporotic target, tartrate-resistant acid phosphatase (TRAP), as well as other potential therapeutical targets for osteoporosis. These results suggest that an intelligent nanoplatform targeting OCs is a promising strategy for osteoporosis therapy.

Retrospective Study of Minimal Three-Year Follow-Up of Transforaminal Endoscopic Discectomy for Lumbar Disc Herniation: 5000 Multicenter Cases.

Objective The objective of this study was to investigate the long-term effects of percutaneous transforaminal endoscopic lumbar discectomy (PTELD) and clarify the differences between outside-in and inside-out techniques. Methodology This was a multicenter retrospective study with a chart review of questionnaires about patients' quality of life. Patients were recruited from three hospitals in China. Based on certain inclusion and exclusion criteria, we enrolled in the study 5000 patients aged ≥18 years diagnosed with lumbar disc herniation who received PTELD from September 2015 to September 2019. The outside-in technique (n=2039) was compared with the inside-out technique for PTELD (n=1890) on the Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and the Short Form 36 (SF-36) of the Health Survey Questionnaire (physical component) both pre-operatively and post-operatively. Results VAS, ODI, and SF-36 significantly improved just after surgery for both techniques compared with pre-operative status. Nevertheless, significant differences existed between the two techniques concerning VAS for leg pain, VAS for back pain, ODI, and SF-36 at 0.5 months post-operatively. The above indices steadily improved within six months after both techniques, after which they did not significantly improve. In detail, outside-in patients suffered more back pain and worse ODI and SF-36 (physical) but had more relief from leg pain 0.5 months after surgery in terms of VAS. As for recovery rate from symptoms, there were only significant differences in recovery rate for leg pain and back pain at the first 1.5 months post-operatively. As for satisfaction rates, the outside-in technique had better results than the inside-out technique at both 0.5 months and 12 months. Conclusion Both techniques could relieve the symptoms of lumbar disc herniation. However, patients in the outside-in group suffered more back pain and a bigger risk of nerve injury than those in the inside-out group.

USP14 promotes pyroptosis of human annulus fibrosus cells derived from patients with intervertebral disc degeneration through deubiquitination of NLRP3.

Intervertebral disc degeneration (IVDD) is a general disorder that results in low back pain and disability among many affected individuals. However, the current treatments for IVDD are limited to relieving the symptoms but do not solve the fundamental issue. In this study, the role of USP14 in mediating the activation of the NLRP3 inflammasome and the pyroptosis of AF cells from IVDD patients is determined in vitro, and gain- and loss-of-function assays of USP14 and the NLRP3 inflammasome are conducted. Pyroptosis of AF cells is detected by flow cytometry. The inflammatory cytokines (IL-1ß and IL-18) and protein levels of NLRP3, active Caspase-1, Aggrecan, MMP3 and ADAMTS-5 are determined by ELISA and western blot analysis, respectively. The correlation between USP14 and NLRP3 is measured by coimmunoprecipitation and ubiquitination analysis. Upregulation of USP14 is accompanied by increased level of the NLRP3 inflammasome in AF cells from IVDD patients; furthermore, a positive correlation between them is observed. USP14 knockdown inhibits pyroptosis in AF cells by inducing ubiquitination of NLRP3, while overexpression of USP14 has the opposite effect, which is inhibited by the NLRP3 inflammasome inhibitor INF39. USP14 exerts its positive regulatory effect on AF cell pyroptosis by modulating the NLRP3/Caspase-1/IL-1ß and IL-18 signaling axes.

Oblique Lateral Endoscopic Decompression and Interbody Fusion for Severe Lumbar Spinal Stenosis: Technical Note and Preliminary Results.

OBJECTIVE: Adequacy of decompression for oblique lateral interbody fusion (OLIF) is a real concern in patients with severe lumbar spinal stenosis (LSS). With this in mind, we combined OLIF with spinal endoscopic technique to achieve a solid fusion and an adequate decompression after one operation. METHODS: This is a technical note. The theoretical basis and operation process of this technique were introduced, and consecutive cases were retrospectively collected. Consecutive patients diagnosed with monosegmental severe LSS (L4/5) and underwent oblique lateral endoscopic decompression and interbody fusion (OLEDIF) from January 2018 to February 2020 were retrospectively collected. Clinical outcomes were assessed by claudication distance, Visual Analog Scale (VAS), and Oswestry Disability Index (ODI) scores. Secondary indicators included operation time, operative blood loss, and postoperative complications. RESULTS: Ten patients were selected for the OLEDIF procedure. They were five women and five men ranging in age from 49 to 75 years (mean age of 63.9 years) and in BMI from 25.4 to 30.2 kg/m2 (mean BMI of 27.5 kg/m2 ). The preoperative claudication distance was 160.00 ± 68.96 m (range 70-250 m), which was significantly extended on the 3-month and 1-year follow-up (1020.00 ± 407.70 m and 1040.00 ± 416.87 m, respectively). The preoperative VAS score of back pain and radiating leg pain was 5.50 ± 0.97 (range 4-7) and 6.40 ± 0.97 (range 5-8). The score on postoperative month 3 was 1.60 ± 0.52 (range 1-2) and 1.20 ± 0.79 (range 0-2), and the 1-year follow-up score was 1.90 ± 0.74 (range 1-3) and 1.60 ± 0.70 (range 1-3), respectively. The preoperative ODI was 72.23 ± 6.30 (range 64.4-82.2), the 3-month follow-up ODI was 31.12 ± 4.20 (range 24.4-35.6), and the 1-year follow-up ODI was 29.33 ± 5.92 (range 20.0-37.8). Compared with the transforaminal lumbar interbody fusion (TLIF) in the literature, the operation time was not prolonged (189.3 ± 32.5 min vs. 214.9 ± 60.0 min) but the amount of blood loss decreased significantly (113.3 ± 26.7 ml vs. 366.8 ± 298.2 ml). No complications were found except one case presented with dysesthesia of the left leg. Imaging results showed good fusion without cage subsidence during 1-year follow-up. CONCLUSION: OLEDIF can achieve complete ventral decompression of the spinal canal and solid fusion of the lumbar spine at one time. It is an effective minimally invasive technique for the treatment of monosegmental severe LSS, which is promising and worthy of further clinical practice.

Comprehensive bioinformatics analyses reveal immune genes responsible for altered immune microenvironment in intervertebral disc degeneration.

We sought to identify novel biomarkers and related mechanisms that might shape the immune infiltration in IDD, thereby providing novel perspective for IDD diagnosis and therapies. Gene expression data sets GSE124272 (for initial analysis) and GSE56081 (for validation analysis) involving samples from IDD patients and healthy controls were retrieved from the Gene Expression Omnibus (GEO) database. Immune genes associated with IDD were identified by GSEA; module genes that exhibited coordinated expression patterns and the strongest positive or negative correlation with IDD were identified by WGCNA. The intersection between immune genes and module genes was used for LASSO variable selection, whereby we obtained pivotal genes that were highly representative of IDD. We then correlated (Pearson correlation) the expression of pivotal genes with immune cell proportion inferred by CIBERSORT algorithm, and revealed the potential immune-regulatory roles of pivotal genes on the pathogenesis of IDD. We discovered several immune-associated pathways in which IDD-associated immune genes were highly clustered, and identified two gene modules that might promote or inhibit the pathogenesis of IDD. These candidate genes were further narrowed down to 8 pivotal genes, namely, MSH2, LY96, ADAM8, HEBP2, ANXA3, RAB24, ZBTB16 and PIK3CD, among which ANXA3, MSH2, ZBTB16, LY96, PIK3CD, ZBTB16, and ADAM8 were revealed to be correlated with the proportion of CD8 T cells and resting memory CD4 T cells. This work identified 8 pivotal genes that might be involved in the pathogenesis of IDD through triggering various immune-associated pathways and altering the composition of immune and myeloid cells in IDD patients, which provides novel perspectives on IDD diagnosis and treatment.

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer.

Reversal of cancer drug resistance remains a critical challenge in chemotherapy. Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer. To overcome the intrinsic limitations in conventional mitochondrial targeting strategies, we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin (DOX) resistance in lung cancer. Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors. As a consequence, thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice. This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

Liensinine Inhibits Osteosarcoma Growth by ROS-Mediated Suppression of the JAK2/STAT3 Signaling Pathway.

Osteosarcoma (OS) is the most common malignancy of bone. Liensinine exerts antitumor effects on cancers of the colon, breast, and gallbladder. However, its antitumor activity in OS remains unclear. This study is aimed at investigating the efficacy of liensinine against OS and the underlying mechanism of action. Cell proliferation, apoptosis, and cycle arrest in OS were detected using the Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays, respectively. The production of reactive oxygen species (ROS), glutathione (GSH) and glutathione disulfide (GSSG) concentrations, and mitochondrial membrane potential (MMP) of OS cells were measured by flow cytometry, colorimetry, and JC-1 staining. The expressions of factors related to apoptosis, cell cycle, and activation of the JAK2/STAT3 pathway were determined by Western blotting. To examine the potential role of ROS, an antioxidant (N-acetyl cysteine, NAC) was used in combination with liensinine. In vivo, we generated a xenograft mouse model to assess its antitumor efficacy. Tissue level expressions of factors related to apoptosis and activation of the JAK2/STAT3 pathway were assessed by immunohistochemistry or Western blotting. Liensinine inhibited the proliferation and induced G0/G1 phase arrest and apoptosis of OS cells in a dose-dependent manner. Additionally, liensinine promoted intracellular ROS production, enhanced the GSSG/GSH ratio, and induced MMP loss and ROS-mediated suppression of the JAK2/STAT3 pathway. NAC significantly attenuated the liensinine-induced antitumor activities and activated the JAK2/STAT3 pathway. In vivo, liensinine effectively inhibited the OS growth and promoted apoptosis; however, it had no negative effect on the internal organs. In conclusion, liensinine-induced ROS production could suppress the activation of the JAK2/STAT3 pathway and inhibit the OS growth both in vivo and in vitro. Our findings provided a new rationale for subsequent academic and clinical research on OS treatment.

Delayed massive cerebral infarction after perioperative period of anterior cervical discectomy and fusion: A case report.

BACKGROUND: Cerebral infarction is an extremely rare postoperative complication of anterior cervical discectomy and fusion (ACDF), particularly in the delayed setting. We present a case who had a sudden stroke on day 18 after surgery. By sharing our experience with this case, we hope to provide new information about stroke after anterior cervical surgery. CASE SUMMARY: We present the case of a 61-year-old man with more than 20 years of hypertension and 14 years of coronary heart disease who had suffered a stroke 11 years ago. The patient was admitted for a multiple ACDF due to symptoms of cervical spondylotic myelopathy and had a sudden stroke on day 18 after surgery. Imaging findings showed a large-area infarct of his left cerebral hemisphere and thrombosis in his left common carotid artery. With the consent of his family, the thrombus was removed and a vascular stent was implanted through an interventional operation. Forty days later, the patient was transferred to a rehabilitation hospital for further treatment. He had normal consciousness but slurred speech at the 1-year follow-up evaluation. The motor and sensory functions of his hemiplegic limbs partially recovered. CONCLUSION: This case illustrated that a postoperative stroke related to anterior cervical surgery may be attributed to prolonged carotid retraction and might have a long silent period. Preventive measures include careful preoperative and postoperative examination for high-risk patients as well as gentle and intermittent retraction of carotid artery sheath during operation.

VPS34 regulates dynamin to determine the endocytosis of mitochondria-targeted zinc oxide nanoparticles in human osteosarcoma cells.

In our previous study, zinc oxide nanoparticles (ZnO NPs) presented satisfying therapeutic effects with cancer cell selectivity in osteosarcoma cells and, thus, have been considered as a potential nanomedicine for human osteosarcoma treatment. However, the poorly investigated internalization process, including their endocytic pathway into tumor cells and intracellular fate, limits the clinical application. Here, we further clarified these aspects. First, ZnO NPs were rapidly internalized by osteosarcoma cells and accumulated in mitochondria, before being entrapped into lysosomes. Second, dynasore (a dynamin inhibitor) was demonstrated to be the most effective in blocking ZnO NP uptake and rescuing ZnO NP-induced osteosarcoma cell autophagic death and apoptosis. Third, we confirmed the key role of dynamin 2 in ZnO NP endocytosis and subsequent autophagic cell death in vitro and in vivo. Furthermore, we proved that VPS34 transferred from cell cytoplasm to cell membrane to interact with dynamin under ZnO NP treatment. Altogether, combined with our previous study, the current research further revealed that ZnO NPs entered human osteosarcoma cells through the VPS34/dynamin 2-dependent endocytic pathway, directly targeting and damaging the mitochondria before being entrapped into the lysosomes, thereby initiating mitophagy-Zn2+-reactive oxygen species-mitophagy axis mediated cell apoptosis.

D-arginine-loaded metal-organic frameworks nanoparticles sensitize osteosarcoma to radiotherapy.

Osteosarcoma is a common type of bone cancers with a high rate of pulmonary recurrence. High-dose radiation therapy is useful for the ablation of unresectable osteosarcoma. However, it may cause severe adverse effects. To address this problem, we developed D-arginine-loaded metal-organic frameworks (MOF) nanoparticles for improving the radiosensitivity of osteosarcoma. D-arginine, a metabolically inert enantiomer of L-arginine, could produce nitric oxide and down-regulate hypoxia-inducible factor-1alpha (HIF-1α) to alleviate tumor hypoxia. In addition, MOF could also generate free radicals to kill the tumor cells. Results demonstrate that D-arginine-loaded nanoparticles enhanced tumor ablation and prevented the lung metastasis in mice upon radiation therapy. Furthermore, the nanoparticles or radiation alone had relatively low toxicity in cells and mice. Therefore, D-arginine-loaded MOF nanoparticles are relatively safe and highly effective in sensitizing osteosarcoma to radiotherapy.

HIF-1α-Mediated Mitophagy Determines ZnO Nanoparticle-Induced Human Osteosarcoma Cell Death both In Vitro and In Vivo.

Although ZnO nanoparticles (NPs) can kill human osteosarcoma cells, the underlying upstream regulatory mechanisms remain unclear. Since hypoxia inducible factor-1α (HIF-1α) regulates the tumor microenvironment, here we explored the interplay between HIF-1α regulation and mitophagy in ZnO NP-induced osteosarcoma inhibition both in vivo and in vitro. We found that ZnO NPs upregulated HIF-1α protein levels when they killed four common human osteosarcoma cell lines. This finding was consistent with our observations that additional HIF-1α upregulation by a hypoxia inducer CoCl2 or under a 1% hypoxia environment enhanced NP-induced cell death, but concurrent HIF-1α suppression by a hypoxia inhibitor YC-1 or HIF-1α siRNA inhibited NP-induced cell death. We discovered an interplay between HIF-1α and the autophagy-Zn2+-reactive oxygen species (ROS)-autophagy cycle axis and revealed that NP-induced cancer cell killing followed a HIF-1α-BNIP3-LC3B-mediated mitophagy pathway. We confirmed that NP-upregulated HIF-1α protein expression was attributed to prolyl hydroxylase inhibition by both ROS and Zn2+. In addition, the in vivo assay confirmed the therapeutic effectiveness and safety of ZnO NPs on a nude mice osteosarcoma model. Collectively, our findings clarified the upstream regulatory mechanism of autophagy induced by the NPs and further demonstrated their antitumor ability in vivo. This work provides new targets and strategies for enhancing NP-based osteosarcoma treatment.

Building block osteotomy, a new back muscle-preserving laminoplasty for lumbar spinal stenosis.

In order to preserve paravertebral muscles and posterior ligaments complex (PLC), this paper proposes a new lumbar laminoplasty surgery for lumbar spinal stenosis (LSS). According to the anatomy of back muscles insertions, building block osteotomy (BBO) which aimed to achieve precise osteotomy and reconstruction based on modular design theory was firstly put forward, and supposed to be achieved by an ultrasound bone scalpel (UBS). In details, lumbar spinous processes are longitudinally split, then supraspinous and interspinous ligaments are sharply cut off longitudinally. After converting to lumbar flexion, lamina osteotomy is innovatively finished by an UBS through interspinous space. After decompression, hollow screws are firstly suggested to be used on each side to fix lamina and spinous processes, and PLC is reconstructed by interrupted suture. Feasibility of this method is evaluated in details. Challenges, advantages and disadvantages are also discussed.

From clinic to hypothesis, an innovative operation for the treatment of lumbar spinal stenosis in a minimal invasive way.

Concerning the damage to back muscles and posterior ligament complex (PLC) by posterior open approach for lumbar spinal stenosis (LSS), the oblique lateral intervertebral fusion (OLIF) is pretty popular nowadays. However, oblique lateral approach has obvious drawbacks, which are limited vision and operative scope for achieving spinal canal decompression. Herein, we present a hypothesis that lumbar canal decompression can be well achieved by OLIF combined with spinal endoscope operative system. Nerval decompression and spinal reconstruction are achieved in a minimal invasive way, which may play an instructive role for the treatment of serious LSS.

LncRNA XIST Promotes Growth of Human Chordoma Cells by Regulating miR-124-3p/iASPP Pathway.

INTRODUCTION: Chordoma is a malignant primary bone tumor that is found in the spine and skull. X-inactive specific transcript (XIST) is a long non-coding RNA (lncRNA) is known to be involved in the development of various cancers, but its precise function and mechanism in human chordoma have not been elucidated. Here, we investigated the role of lncRNA XIST in chordoma progression. METHODS: Quantitative real time-polymerase chain reaction (qRT-PCR) was performed to determine lncRNA XIST expression in human chordoma tissues and matched-noncancerous tissues. Western blot was used to determine protein expression. Silencing and overexpression of lncRNA XIST were carried out by RNA interference (RNAi) and lentiviral transduction, respectively. Cell Counting Kit-8 (CCK-8) assay and flow cytometry were employed to examine the effects of lncRNA XIST on growth of human chordoma cells. Lastly, the role of lncRNA XIST in vivo was explored using a xenograft model. RESULTS: We found that lncRNA XIST expression was upregulated in chordoma and strongly correlated with poor patient prognosis. Moreover, lncRNA XIST promoted proliferation and inhibited apoptosis of chordoma cells. Mechanistically, upregulation of lncRNA XIST led to a decrease in miR-124-3p expression, thereby promoting the expression of the miR-124-3p target gene, inhibitor of apoptosis-stimulating protein of p53 (iASPP). Addition of miR-124-3p inhibitor or mimic reversed the effects induced by lncRNA XIST silencing or overexpression on chordoma cell proliferation. Lastly, using a xenograft mouse model, we found that silencing of lncRNA XIST decreased tumorigenicity in vivo, as shown by increased tumor cell apoptosis. CONCLUSION: Our findings demonstrate a key role for lncRNA XIST in chordoma progression by regulating miR124-3p/iAPSS pathway.

Microstructure study of normal lunates with micro-computed tomography.

In order to study the microstructure characteristics of normal lunate bones, eight fresh cadaver normal lunates were scanned with micro-computed tomography. High-resolution images of the micro-structure of normal lunates were obtained and we analyzed the nutrient foramina. Then nine regions of interest (ROI) were chosen in the central sagittal plane so that we could obtain the parameters of trabecular bones of ROIs. The distal lamellar-like compact structure had statistically significant differences when it was compared with the ROIs in the volar and dorsal ends of the distal cortex. The difference of diameter between the volar and dorsal foramina was significant (P<0.05). However, there was no significant difference regarding the number. The trabecular bones of the volar and dorsal distal ends had lower intensity than those of the distal central subchondral bone plate. The diameters of the nutrient foramina on the volar cortex were larger than those on the dorsal. This research provided more detailed information about microstructure of normal lunate and the nutrient foramina on cortex, and a reference for further study about diseased lunate.