Macrophages facilitate peripheral nerve regeneration by organizing regeneration tracks through Plexin-B2.

The regeneration of peripheral nerves is guided by regeneration tracks formed through an interplay of many cell types, but the underlying signaling pathways remain unclear. Here, we demonstrate that macrophages are mobilized ahead of Schwann cells in the nerve bridge after transection injury to participate in building regeneration tracks. This requires the function of guidance receptor Plexin-B2, which is robustly up-regulated in infiltrating macrophages in injured nerves. Conditional deletion of Plexin-B2 in myeloid lineage resulted in not only macrophage misalignment but also matrix disarray and Schwann cell disorganization, leading to misguided axons and delayed functional recovery. Plexin-B2 is not required for macrophage recruitment or activation but enables macrophages to steer clear of colliding axons, in particular the growth cones at the tip of regenerating axons, leading to parallel alignment postcollision. Together, our studies unveil a novel reparative function of macrophages and the importance of Plexin-B2-mediated collision-dependent contact avoidance between macrophages and regenerating axons in forming regeneration tracks during peripheral nerve regeneration.

Targeting foamy macrophages by manipulating ABCA1 expression to facilitate lesion healing in the injured spinal cord.

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDMϕ) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy Mϕ), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy Mϕ and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by Mϕ, plays a crucial role in lipid efflux from foamy cells. We observed that foamy Mϕ lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy Mϕ as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy Mϕ, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy Mϕ, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy Mϕ in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.

Nanoenzyme-Reinforced Multifunctional Scaffold Based on Ti3C2Tx MXene Nanosheets for Promoting Structure-Functional Skeletal Muscle Regeneration via Electroactivity and Microenvironment Management.

The completed volumetric muscle loss (VML) regeneration remains a challenge due to the limited myogenic differentiation as well as the oxidative, inflammatory, and hypoxic microenvironment. Herein, a 2D Ti3C2Tx MXene@MnO2 nanocomposite with conductivity and microenvironment remodeling was fabricated and applied in developing a multifunctional hydrogel (FME) scaffold to simultaneously conquer these hurdles. Among them, Ti3C2Tx MXene with electroconductive ability remarkably promotes myogenic differentiation via enhancing the myotube formation and upregulating the relative expression of the myosin heavy chain (MHC) protein and myogenic genes (MyoD and MyoG) in myogenesis. The MnO2 nanoenzyme-reinforced Ti3C2Tx MXene significantly reshapes the hostile microenvironment by eliminating reactive oxygen species (ROS), regulating macrophage polarization from M1 to M2 and continuously supplying O2. Together, the FME hydrogel as a bioactive multifunctional scaffold significantly accelerates structure-functional VML regeneration in vivo and represents a multipronged strategy for the VML regeneration via electroactivity and microenvironment management.

miR-145a-5p/Plexin-A2 promotes the migration of OECs and transplantation of miR-145a-5p engineered OECs enhances the functional recovery in rats with SCI.

BACKGROUND: Olfactory ensheathing cells (OECs) serve as a bridge by migrating at the site of spinal cord injury (SCI) to facilitate the repair of the neural structure and neural function. However, OEC migration at the injury site not only faces the complex and disordered internal environment but also is closely associated with the migration ability of OECs. METHODS: We extracted OECs from the olfactory bulb of SD rats aged <7 days old. We verified the micro ribonucleic acid (miR)-145a-5p expression level in the gene chip after SCI and OEC transplantation using quantitative reverse transcription (qRT)-polymerase chain reaction (PCR). The possible target gene Plexin-A2 of miR-145a-5p was screened using bioinformatics and was verified using dual-luciferase reporter assay, Western blot, and qRT-PCR. The effect of miR-145a-5p/plexin-A2 on OEC migration ability was verified by wound healing assay, Transwell cell migration assay, and immunohistochemistry. Nerve repair was observed at the injured site of the spinal cord after OEC transplantation using tissue immunofluorescence and magnetic resonance imaging, diffusion tensor imaging, and the Basso-Beattie-Bresnahan locomotor rating scale were further used for imaging and functional evaluation. RESULTS: miR-145a-5p expression in the injured spinal cord tissue after SCI considerably decreased, while Plexin-A2 expression significantly increased. OEC transplantation can reverse miR-145a-5p and Plexin-A2 expression after SCI. miR-145a-5p overexpression enhanced the intrinsic migration ability of OECs. As a target gene of miR-145a-5p, Plexin-A2 hinders OEC migration. OEC transplantation overexpressing miR-145a-5p after SCI can increase miR-145a-5p levels in the spinal cord, reduce Plexin-A2 expression in the OECs and the spinal cord tissue, and promote OEC migration and distribution at the injured site. OEC transplantation overexpressing miR-145a-5p can promote the repair of neural morphology and neural function. CONCLUSIONS: Our study demonstrated that miR-145a-5p could promote OEC migration by down-regulating the target gene Plexin-A2, and transplantation of miR-145a-5p engineered OECs was beneficial to enhance neural structural and functional recovery in SCI rats.

ZIM3 activation of CCL25 expression in pulmonary metastatic nodules of osteosarcoma recruits M2 macrophages to promote metastatic growth.

Tumor-associated macrophages (TAMs) play an important role in tumor growth and metastasis. However, the involvement of TAMs infiltration in pulmonary osteosarcoma (OS) metastasis remains poorly understood. Therefore, the effect of OS cells on macrophages migration was investigated by in vivo and in vitro experiments to evaluate the infiltration and mechanism of TAMs in pulmonary OS metastases. The results showed that the zinc finger protein ZIM3 was upregulated in OS cells than in osteoblasts and activated the expression of CCL25, which subsequently promoted the migration of M2 macrophages. CCL25 or ZIM3 silencing in OS cells inhibited the infiltration of M2 macrophages and the formation of pulmonary metastatic nodules in a mouse model of pulmonary OS metastasis and prolonged the survival of the mice. Furthermore, bioinformatics analyses revealed that CCL25 and ZIM3 expressions are negatively correlated with the prognosis of OS patients. In conclusion, this study found that a large number of M2 TAMs were recruited into pulmonary metastatic nodules of OS through the activation of the ZIM3-CCL25 axis in OS cells, thereby facilitating OS metastasis. Therefore, the suppression of ZIM3-CCL25-induced recruitment of M2 TAMs to the metastatic sites might be considered as a therapeutic approach to inhibit the growth of pulmonary OS metastases.

Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer.

Rationale: The current molecular classification of small-cell lung cancer (SCLC) on the basis of the expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. Objectives: To refine the current SCLC classification with epigenomic profiles and to identify features of the redefined SCLC subtypes. Methods: We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9)-mediated deletion. NKX2-1-specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox; Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized. Measurements and Main Results: We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. In addition, we found that maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aα subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.

MicroRNA-137-mediated lysine demethylase 4A regulates the recovery of spinal cord injury via the SFRP4-Wnt/ß-Catenin axis.

OBJECTIVE: Spinal cord injury (SCI) causes great harm to the normal life of patients. Histone demethylase is involved in many biological processes, including SCI. Hence, this study explored the role and mechanism of histone lysine demethylase 4A (KDM4A) in SCI. METHODS: The acute SCI (ASCI) rat model was established after spinal compression and the SCI neuronal model was induced via treating PC12 cells with lipopolysaccharide (LPS). KDM4A expression during SCI was detected. The microRNA (miRNA) targeting KDM4A was predicted and verified. The miRNA and KDM4A expression patterns were intervened in LPS-stimulated PC12 cells to evaluate their combined effects on neuronal cells in SCI. The downstream pathways of KDM4A were predicted, and SFRP4 and H3K9me3 expressions were determined. After the intervention of SFRP4 in LPS-treated cells, ß-Catenin expression and the effect of SFRP4 on neuronal cells in SCI were detected. Finally, the effectiveness of the miR-137/KDM4A/SFRP4/Wnt/ß-Catenin axis was verified in vivo. RESULTS: KDM4A was abnormally elevated in SCI. miR-137 targeted KDM4A. miR-137 effectively inhibited the apoptosis of LPS-challenged PC12 cells, which could be reversed after overexpressing KDM4A. KDM4A promoted SFRP4 expression through demethylation of H3K9me3. Overexpression of SFRP4 blocked the Wnt/ß-Catenin pathway and promoted apoptosis of LPS-stimulated cells. In vivo, miR-137 overexpression remarkably improved SCI symptoms, accompanied by obviously increased ß-Catenin expression and notably decreased KDM4A and SFRP4 expressions, while overexpressed KDM4A treatment showed the opposite trend in the presence of miR-137. CONCLUSION: We demonstrated that miR-137 targeted KDM4A and then downregulated SFRP4 to ameliorate SCI in a Wnt/ß-Catenin-dependent manner.

Chemogenetic stimulation of proprioceptors remodels lumbar interneuron excitability and promotes motor recovery after SCI.

Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.

Prophylactic Use of Antibiotics for Fever After Drainage Removal Following a Dural Tear During Lumbar Spinal Surgery: A Retrospective Study.

BACKGROUND Dural tear and subsequent cerebrospinal fluid leakage are frequent complications during lumbar spine surgery. This retrospective study aimed to investigate the risk factors and the use of prophylactic antibiotics in patients with fever after drainage removal (FDR) following lumbar dural tear during lumbar spinal surgery. MATERIAL AND METHODS The authors retrospectively analyzed 2812 patients who underwent different spinal surgical procedures from January 2015 to December 2017. The basic information of patients was obtained to analyze the risk factors of dural tear and FDR. The patients were divided into 5 groups according to their antibiotic strategies for FDR (no antibiotics, ceftriaxone, vancomycin, ceftriaxone+vancomycin, other antibiotics). Body temperature, laboratory test results, and pathogen profiles were collected for analysis. RESULTS There were 326 cases diagnosed as dural tear, including 198 cases of FDR. Sex, age, type of disease, and previous lumbar surgery played significant roles in the dural tear rate (P<0.05). Patients older than 60 years old had a higher incidence of FDR after dural tear (P<0.05). There was no significant difference in the incidence of surgical site infection among the various treatment groups (P>0.05). CONCLUSIONS Age has obvious effect on dural tear and FDR, whereas sex, revision surgery, primary diagnosis, and procedure type only affect the rate of dural tear. The prophylactic use of antibiotics has no effect on the incidence of surgical site infection when fever after drainage removal occurred in patients with dural tear.

Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway.

microRNA-126 (miR-126), an endothelial-specific miRNA, is associated with vascular homeostasis and angiogenesis. However, the efficiency of miR-126-based treatment is partially compromised due to the low efficiency of miRNA delivery in vivo. Lately, exosomes have emerged as a natural tool for therapeutic molecule delivery. Herein, we investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) can be utilized to deliver miR-126 to promote angiogenesis. Exosomes were isolated from BMMSCs overexpressed with miR-126 (Exo-miR-126) by ultracentrifugation. In vitro study, Exo-miR-126 treatment promoted the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, the gene/protein expression of angiogenesis-related vascular endothelial growth factor (VEGF) and angiotensin-1 (Ang-1) were up-regulated after incubation with Exo-miR-126. Additionally, the expression level of phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) showed an inverse correlation with miR-126 in HUVECs. Particularly, the Exo-miR-126 treatment contributed to enhanced angiogenesis of HUVECs by targeting PIK3R2 to activate the PI3K/Akt signalling pathway. Similarly, Exo-miR-126 administration profoundly increased the number of newly formed capillaries in wound sites and accelerated the wound healing in vivo. The results demonstrate that exosomes derived from BMMSCs combined with miR-126 may be a promising strategy to promote angiogenesis.

The let-7f-5p-Nme4 pathway mediates tumor necrosis factor α-induced impairment in osteogenesis of bone marrow-derived mesenchymal stem cells.

Although tumor necrosis factor α (TNF-α)-mediated inflammation significantly impacts osteoporosis, the mechanisms underlying the osteogenic differentiation defects of bone marrow-derived mesenchymal stem cells (BM-MSCs) caused by TNF-α remain poorly understood. We found that TNF-α stimulation of murine BM-MSCs significantly upregulated the expression levels of several microRNAs (miRNAs), including let-7f-5p, but this increase was significantly reversed by treatment with the kinase inhibitor BAY 11-7082. To study gain- or loss of function, we transfected cells with an miRNA inhibitor or miRNA mimic. We then demonstrated that let-7f-5p impaired osteogenic differentiation of BM-MSCs in the absence and presence of TNF-α, as evidenced by alkaline phosphatase and alizarin red staining as well as quantitative assays of the mRNA levels of bone formation marker genes in differentiated BM-MSCs. Moreover, let-7f-5p targets the 3' untranslated region of Nucleoside diphosphate kinase 4 (Nme4) mRNA and negatively regulates Nme4 expression in mouse BM-MSCs. Ectopic expression of Nme4 completely reversed the inhibitory effects of the let-7f-5p mimic on osteogenic differentiation of mouse BM-MSCs. Furthermore, inhibition of let-7f-5p or overexpression of Nme4 in BM-MSCs restored in-vivo bone formation in an ovariectomized animal model. Collectively, our work indicates that let-7f-5p is involved in TNF-α-mediated reduction of BM-MSC osteogenesis via targeting Nme4.

Lithium alleviated spinal cord injury (SCI)-induced apoptosis and inflammation in rats via BDNF-AS/miR-9-5p axis.

Spinal cord injury (SCI) is a major cause of paralysis, disability and even death in severe cases. Lithium has neuroprotective effects on SCI, while the underlying mechanisms remain obscure. In the present study, we established a SCI rat model, which subsequently received lithium treatment. Results displayed that lithium treatment improved the locomotor function recovery and reduced apoptosis by increasing anti-apoptotic molecule expression and decreasing pro-apoptotic factor expression in SCI rats. Furthermore, lithium treatment alleviated the inflammatory response by inactivating the nuclear factor-kappa B (NF-κB) pathway and inhibited the expression of lncRNA brain-derived neurotrophic factor antisense (BDNF-AS) in SCI rats. Subsequent researches indicated that miR-9-5p was targeted and regulated by BDNF-AS. Lithium treatment rescued the upregulation of BDNF-AS expression and downregulation of miR-9-5p expression induced by H2O2 in SH-SY5Y cells. BDNF-AS overexpression or miR-9-5p interference attenuated the anti-apoptotic and anti-inflammatory effects of lithium chloride in SH-SY5Y cells that was damaged by H2O2 induction, revealing that lithium might act through the BDNF-AS/miR-9-5p axis. In vivo studies showed that the injection of BDNF-AS adenovirus vector or miR-9-5p inhibitor reversed the effects of lithium on the histologic morphology of spinal cord, motor function, inflammatory reaction and apoptosis in SCI rats, which was consistent with the results of in vitro studies. In conclusion, our data demonstrated that lithium reduced SCI-induced apoptosis and inflammation in rats via the BDNF-AS/miR-9-5p axis.

Methane attenuates lung ischemia-reperfusion injury via regulating PI3K-AKT-NFκB signaling pathway.

Objective: This study aims to investigate the protective effects and possible mechanism of methane-rich saline (MS) on lung ischemia-reperfusion injury (LIRI) in rats.Methods: MS (2 ml/kg and 20 ml/kg) was injected intraperitoneally in rats after LIRI. Lung injury was assayed by Hematoxylin-eosin (HE) staining and wet-to-dry weight (W/D). The cells in the bronchoalveolar lavage fluid (BALF) and blood were counted. Oxidative stress was examined by the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-10 (IL-10) were determined by ELISA. Lung tissue apoptosis was detected by TUNEL staining and western blotting of Bcl-2, Bax, and caspase-3. The expressions of IкBα, p38, PI3K, AKT, and NF-κB were analyzed with Western blotting.Results: MS effectively decreased the lung W/D ratio as well as the lung pathological damage and reduced the localized infiltration of inflammatory cells. Methane suppressed the expression of the PI3K-AKT-NFκB signaling pathway during the lung IR injury, which inhibited the activation of NF-kB and decreased the level of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-10. Moreover, we found that MS treatment relieved reactive oxygen species (ROS) damage by downregulating MDA and upregulating SOD. MS treatment also regulated apoptosis-related proteins, such as Bcl-2, Bax, and caspase-3.Conclusions: MS could repair LIRI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis via the PI3K-AKT-NFκB signaling pathway, which may provide a novel and promising strategy for the treatment of LIRI.

Nomograms for predicting overall survival and cancer-specific survival of chondroblastic osteosarcoma patients.

BACKGROUND: The establishment of precise and personalized prediction systems for chondroblastic osteosarcoma patients is important for guiding the treatment. METHODS: The univariate logrank test and multivariate Cox regression analysis were performed to identify independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Nomograms were constructed to estimate the OS and CSS based on these factors. Internal and external validation was performed. The predictive power of the nomograms was determined by C-index and calibration plots. RESULTS: A total of 401 chondroblastic osteosarcoma cases were identified. Univariate and multivariate analysis revealed that age at diagnosis, histological grade, tumor size, Surveillance, Epidemiology, and End Results stage, and surgical resection were independent prognostic factors for OS and CSS. The five factors were incorporated to construct the nomograms for estimating the 3- and 5-year OS and CSS. The C-index values for the internal validation of the OS and CSS nomogram were 0.732 and 0.746, respectively, and for the external validation were 0.780 and 0.808, respectively. The calibration curves revealed that the predicted OS and CSS could well match the actual survival rate. CONCLUSIONS: The nomograms for predicting 3- and 5-year OS and CSS were constructed and were proved to be accurate and reliable by the internal and external validation.

Interface Fixation Using Absorbable Screws versus Plate Fixation in Anterior Cervical Corpectomy and Fusion for Two-Level Cervical Spondylotic Myelopathy.

BACKGROUND We compared the clinical and radiographic outcomes between interface fixation using absorbable screws and plate fixation in anterior cervical corpectomy and fusion (ACCF) to evaluate the effectiveness of these 2 fixation methods for the treatment of 2-level cervical spondylotic myelopathy (CSM). MATERIAL AND METHODS From January 2014 to December 2016, a total of 220 patients who received 2-level ACCF were retrospectively collected. Among them, 108 patients were treated with interface fixation using absorbable screws (Group A) and 112 patients underwent plate fixation (Group B). Japanese Orthopedic Association (JOA) score and Neck Disability Index (NDI) score were employed to compare the clinical improvement. Operative time, blood loss, surgical cost, cervical lordosis, complications, and fusion rate were also evaluated. RESULTS The average follow-up time were 35.2±4.5 months in Group A and 35.9±3.9 months in Group B. There was no difference in operative time and blood loss for both groups. The JOA scores and NDI scores were similar in each follow-up (p>0.05 in all). Group A cost an average of 30% less than Group B for the operation. Both groups achieved 100% in the fusion rate with the same conditions in cervical lordosis. Group A (5/108) had a significantly lower complication rate than Group B (17/112) (p<0.05). CONCLUSIONS ACCF with interface fixation using absorbable screws achieved similar clinical outcomes compared to ACCF with plate fixation for 2-level CSM. Moreover, the interface fixation using absorbable screws presented far fewer complications and cost less for the operation.

Biomechanical Comparison of 1-Level Corpectomy and 2-Level Discectomy for Cervical Spondylotic Myelopathy: A Finite Element Analysis.

BACKGROUND Anterior cervical discectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) are effective treatments for cervical spondylotic myelopathy (CSM), but it is unclear which is better. In this study, we compared the biomechanical properties of 2-level ACDF and 1-level ACCF. MATERIAL AND METHODS An intact C3-C7 cervical spine model was developed and validated, then ACDF and ACCF simulation models were developed. We imposed 1.0 Nm moments and displacement-controlled loading on the C3 superior endplate. The range of motions (ROMs) of surgical and adjacent segments and von Mises stresses on endplates, fixation systems, bone-screw interfaces, and bone grafts were recorded. RESULTS ACDF and ACCF significantly reduced the surgical segmental ROMs to the same extent. ACCF induced much lower stress peaks in the fixation system and bone-screw interfaces and higher stress peaks on the bone graft. ACDF induced much lower stress peaks on the C4 inferior endplate and equivalent stress on the C6 superior endplate. There was no difference in the ROMs of surgical and adjacent segments and the intradiscal stress of adjacent levels between ACDF and ACCF. CONCLUSIONS Both ACDF and ACCF can provide satisfactory spinal stability. ACDF may be beneficial for subsidence resistance due to the lower stress peaks on the endplate. The ACCF may perform better in long-term stability and bone fusion owing to the lower stress peaks in the fixation system and bone-screw interfaces, and higher stress peaks in the bone graft.

miR-99b-3p is induced by vitamin D3 and contributes to its antiproliferative effects in gastric cancer cells by targeting HoxD3.

Vitamin D3 is known to have anticancer actions by affecting tumorigenesis including the cell cycle and cell apoptosis in gastric cancer (GC) cells; the genes including microRNAs (miRNAs) regulated by vitamin D3 signaling remain discovered. miR-99b-3p, the tumor suppressor gene, is not only decreased in GC tissues, but is also induced by vitamin D3 through the vitamin D receptor (VDR) binding on the promoter domain of miR-99b. Further study indicates that miR-99b-3p inhibits cell viability and induces cell arrest in the S-phase in GC cells, the direct target gene of miR-99b-3p is verified to be HoxD3, which is also overexpressed in GC cell lines. Overall, our results show that miR-99b-3p mediates the antiproliferative of vitamin D3 in GC cells and might hold promise for prognosis and therapeutic strategies for GC treatment.

Notch1 promotes mouse spinal neural stem and progenitor cells proliferation via p-p38-pax6 induced cyclin D1 activation.

Neural stem and progenitor cells (NSPCs) are important for nerve regeneration after spinal cord injury (SCI). Their proliferation, however, is limited. In this study, we investigated the role of Notch1 signaling in NSPC proliferation using adult mouse spinal cord derived NSPCs. We observed that Notch1 promoted proliferation of NSPCs and that Notch1 overexpression led to an expansion of cells in the S-phase and increased cyclin D1 expression. When investigating the functional relationship between Notch1, p-p38 and Pax6, we found that Notch1 suppressed p-p38 while promoting Pax6 expression. Functional inhibition of p38 with SB202190 led to increased Pax6 expression and to proliferation, as determined by BrdU. Furthermore, we confirmed that Pax6 induced proliferation in adult mouse spinal cord derived NSPCs. In conclusion, we demonstrate that Notch1 promotes the proliferation of mouse spinal NSPCs via a p-p38-pax6-cyclin D1 signaling pathway. This pathway constitutes a promising new therapeutic target for SCI treatment.

Biomechanical Comparison of Integrated Fixation Cage Versus Anterior Cervical Plate and Cage in Anterior Cervical Corpectomy and Fusion (ACCF): A Finite Element Analysis.

BACKGROUND Anterior cervical plate and cage fixation system (ACPC) used in anterior cervical corpectomy and fusion (ACCF) is reported to incur excess complications. This study aimed to introduce integrated fixation cage (IFC) into ACCF to eliminate the anterior cervical plate (ACP)-related complications. MATERIAL AND METHODS One validated intact and 3 ACCF-simulated C3-C7 cervical spine models were developed. In ACCF models, C5 was corpectomied and fixed by IFC or ACPC. For each model, 1.0 Nm moments of flexion, extension, lateral bending, and torsion were imposed on the C3 vertebra. The range of motion (ROM) of each segment and the stress distribution on screw-vertebra interface, bone graft, and cage-endplate were recorded and analyzed. RESULTS ROMs of C3-C7 were not different in any motion condition between IFC and ACPC models. The maximal von Mises stress on screw-vertebra interface of the IFC model was lower than that of the ACPC models in flexion, extension, and lateral bending, but higher in rotation. The maximal von Mises stress on bone graft of the IFC model was higher compared with the ACPC models, except in flexion. The IFC model showed a higher maximal von Mises stress on cage-endplate interface in all motion planes. CONCLUSIONS Based on finite element analysis, IFC provided identical C3-C7 construct stability as ACPC. Compared with ACPC, IFC showed better biomechanical performance on screw-vertebra interface and bone graft, but worse biomechanical performance on cage-endplate interface.

Effect of Dome-Shaped Titanium Mesh Cages on Cervical Endplate Under Cyclic Loading: An In Vitro Biomechanics Study.

BACKGROUND This study aimed to verify the anti-subsidence ability of dome-shaped titanium mesh cage (TMC) used in anterior cervical corpectomy and fusion (ACCF). MATERIAL AND METHODS Thirty fresh human cervical vertebrae specimens were collected and randomly harvested into 2 groups: the traditional TMC group and the dome-shaped TMC group. The bone mineral density (BMD) of the specimens was recorded. Each group was biomechanically tested in axial compression with a cyclically loading range from 60 to 300 N at 0.5Hz for 10 000 cycles. The displacement data of the 2 groups were recorded every 10 cycles. RESULTS There was no significant difference in bone mineral density between the 2 groups of cervical specimens. The traditional TMC group stabilized at 535±35 cycles while the dome-shaped TMC group stabilized at 1203±57 cycles, which showed that the rate of subsidence of the dome-shaped TMC group was significantly slower than that of the traditional TMC group (p<0.05). After reaching stability, both groups had a more gradual and sustained growth. The peak displacement during fatigue testing was -2.064±0.150mm in the traditional TMC group and -0.934±0.086mm in the dome-shaped TMC group, which showed a significant difference (p<0.05). CONCLUSIONS The dome-shaped TMC showed a smaller subsidence displacement and a gentler subsidence tendency following the same cyclic loading (compared to the traditional TMC). From a biomechanical point of view, the dome-shaped TMC has stronger anti-subsidence ability due to its unique structural design that closely matches the vertebral endplate.