Single-Cell RNA Sequencing Pro-angiogenic Macrophage Profiles Reveal Novel Prognostic Biomarkers and Therapeutic Targets for Osteosarcoma.

Osteosarcoma (OS) is a malignant bone tumor that most commonly occurs in children and adolescents. OS patients have a poor prognosis, and 5-year survival rates have rarely improved significantly over the past few decades. OS prognosis may be related to the infiltration of tumor-associated macrophages (TAMs). However, the role of proangiogenic macrophages, a subtype of TAMs, in OS prognosis has not been reported. In this study, seven subtypes of TAMs were identified from single-cell RNA sequencing (scRNA-seq) data that we propose defining as proangiogenic TAMs (Angio-TAMs), interferon-primed TAMs (IFN-TAMs), inflammatory cytokine-enriched TAMs (Inflam-TAMs), immune regulatory TAMs (Reg-TAMs), lipid-associated TAMs (LA-TAMs), and resident-tissue macrophages like TAMs (RTM-TAMs) (containing two subcellular types). In the survival analysis of each macrophage subtype, it was found that patients with Angio-TAMs had the most significant difference in survival. Eight genes associated with Angio-TAMs were obtained by differential expression analysis, and these genes were built into a prognostic model using the LASSO algorithm. Clinical OS case samples were categorized into high-risk and low-risk subgroups using median risk scores. In comparison to the low-risk subgroup, the survival time of the high-risk subgroup was much shorter. Additional studies on immune cell infiltration and immune checkpoint molecule expression in the two risk subgroups were carried out. In immunotherapy response prediction, the Angio-TAM-associated gene risk signature was found to be negatively correlated with immune checkpoint responses. In addition, the associated enriched GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were mainly involved in the malignant progression of tumors. As suggested by these findings, the Angio-TAM gene risk signature may be an underlying prognostic biomarker and novel therapeutic target for OS patients.Kindly check and confirm whether the ESM file is correctly identifiedWe have checked this file and confirmed that it can be correctly identified.

A Novel Defined Necroptosis-Related Genes Prognostic Signature for Predicting Prognosis and Treatment of Osteosarcoma.

Osteosarcoma (OS) is a frequent primary malignant bone tumor, with a poor prognosis. Necroptosis is strongly correlated with OS and may be an influential target for treating OS. This study's objective was to establish a necroptosis-related gene (NRG) prognostic signature that could predict OS prognosis and guide OS treatment. First, we identified 20 NRGs associated with OS survival based on the TARGET database. We then derived a 7 NRG prognostic signature. Our findings revealed that the 7 NRG prognostic signature performed well in predicting the survival of OS patients. We next analyzed differences in immunological status and immune cell infiltration. In addition, we examined the relationship between chemo/immunotherapeutic response and the 7-NRG prognostic signature. In addition, to probe the mechanisms underlying the NRG prognostic signature, we performed functional enrichment assays including GO and KEGG. Finally, CHMP4C was selected for functional experiments. Silencing CHMP4C prevented OS cells from proliferating, migrating, and invading. This 7-NRG prognostic signature seems to be an excellent predictor that can provide a fresh direction for OS treatment.

Unintended dural tears during unilateral biportal endoscopic lumbar surgery: incidence and risk factors.

BACKGROUND: An unintended dural tear (DT) is the most common intraoperative complication of lumbar spine surgery. The unilateral biportal endoscopic technique (UBE) has become increasingly popular for treating various degenerative diseases of the lumbar spine; however, the DT incidence and risk factors specific to UBE remain undetermined. Therefore, this study aimed to evaluate the incidence and risk factors of DTs in UBE. METHOD: Data from all patients who underwent UBE for degenerative lumbar spinal diseases from November 2018 to December 2021 at our institution were used to assess the effects of demographics, diagnosis, and type of surgery on unintended DT risk. RESULTS: Overall, 24/608 patients (3.95%) experienced DTs and were treated with primary suture repair or bed rest. Although several patients experienced mild symptoms of cerebrospinal fluid (CSF) leaks, no serious postoperative sequelae such as nerve root entrapment, meningitis, or intracranial hemorrhage occurred. Additionally, no significant correlations were identified between DT and sex (P = 0.882), body mass index (BMI) (P = 0.758), smoking status (P = 0.506), diabetes (P = 0.672), hypertension (P = 0.187), or surgeon experience (P = 0.442). However, older patients were more likely to experience DT than younger patients (P = 0.034), and patients with lumbar spinal stenosis (LSS) were more likely to experience DT than patients with lumbar disc herniation (LDH) (P = 0.035). Additionally, DT was more common in revision versus primary surgery (P < 0.0001) and in unilateral laminotomy with bilateral decompression (ULBD) versus unilateral decompression (P = 0.031). Univariate logistic regression analysis revealed that age, LSS, ULBD, and revision surgery were significant risk factors for DT. CONCLUSIONS: In this UBE cohort, we found that the incidence of DT was 3.95%. Additionally, older age, LSS, ULBD, and revision surgery significantly increased the risk of DT in UBE surgery.

Myelin Debris Impairs Tight Junctions and Promotes the Migration of Microvascular Endothelial Cells in the Injured Spinal Cord.

Clearance of myelin debris caused by acute demyelination is an essential process for functional restoration following spinal cord injury (SCI). Microvascular endothelial cells, acting as "amateur" phagocytes, have been confirmed to engulf and degrade myelin debris, promoting the inflammatory response, robust angiogenesis, and persistent fibrosis. However, the effect of myelin debris engulfment on the function of endothelial tight junctions (TJs) remains unclear. Here, we demonstrate that myelin debris uptake impairs TJs and gap junctions of endothelial cells in the lesion core of the injured spinal cord and in vitro, resulting in increased permeability and leakage. We further show that myelin debris acts as an inducer to regulate the endothelial-to-mesenchymal transition in a dose-dependent manner and promotes endothelial cell migration through the PI3K/AKT and ERK signaling pathways. Together, our results indicate that myelin debris engulfment impairs TJs and promotes the migration of endothelial cells. Accelerating myelin debris clearance may help maintain blood-spinal cord barrier integrity, thus facilitating restoration of motor and sensory function following SCI.

Unilateral biportal endoscopic extreme transforaminal lumbar interbody fusion with large cage combined with endoscopic unilateral pedicle screw fixation for lumbar degenerative diseases: a technical note and preliminary effects.

OBJECTIVE: The purpose of the study was to investigate the feasibility and preliminary effects of unilateral biportal endoscopic extreme transforaminal lumbar interbody fusion(UBE-eXTLIF) with large cage combined with endoscopic unilateral pedicle screw fixation for lumbar degenerative diseases. METHODS: Patients with lumbar degenerative diseases who received UBE-eXTLIF with large cage combined with endoscopic unilateral pedicle screw fixation from June 2022 to July 2022 were retrospectively analyzed, including 4 females and 1 males. The clinical symptoms and signs were consistent with the imaging changes. We recorded operation time, length of postoperative hospital stay, and complications. Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and modified Macnab scale was used to evaluate the clinical efficacy at preoperative, postoperative 1 month, and the last follow-up. RESULTS: The operation was successfully completed in all cases. The operation time was 150-180 min, with an average of 164.60 ± 12.03 min. No serious complications such as dural tears and vascular and nerve injuries occurred during operation. All the patients got out of bed 1-3 days after surgery and were hospitalized 4-5 days after surgery, with an average of 4.20 ± 0.45 days. Preoperative VAS scores of low back pain were 6.20 ± 0.84 and respectively decreased to 2.20 ± 0.45 and 1.40 ± 0.55 at postoperative 1 month and at the last follow-up, and the difference was statistically significant (P < 0.05). Preoperative VAS scores of lower limb pain were 4.60 ± 2.61 and respectively decreased to 1.00 ± 0.71 and 0.60 ± 0.55 at postoperative 1 month and at the last follow-up, and the difference was statistically significant (P < 0.05). Preoperative ODI scores were 62.00 ± 3.16 and respectively decreased to 38.00 ± 1.41 and 32.40 ± 3.29 at postoperative 1 month and at the last follow-up, and the difference was statistically significant (P < 0.05). According to the modified Macnab criteria, the final outcome was excellent in 4 cases and good in 1 case. Five patients could return to normal activities within 3 weeks. CONCLUSIONS: UBE-eXTLIF with large cage combined with endoscopic unilateral pedicle screw fixation can achieve excellent clinical results and may become a new minimally invasive endoscopic fusion method for lumbar degenerative diseases.

SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRß pathway.

BACKGROUND: Excessively deposited fibrotic scar after spinal cord injury (SCI) inhibits axon regeneration. It has been reported that platelet-derived growth factor receptor beta (PDGFRß), as a marker of fibrotic scar-forming fibroblasts, can only be activated by platelet-derived growth factor (PDGF) B or PDGFD. However, whether the activation of the PDGFRß pathway can mediate fibrotic scar formation after SCI remains unclear. METHODS: A spinal cord compression injury mouse model was used. In situ injection of exogenous PDGFB or PDGFD in the spinal cord was used to specifically activate the PDGFRß pathway in the uninjured spinal cord, while intrathecal injection of SU16f was used to specifically block the PDGFRß pathway in the uninjured or injured spinal cord. Immunofluorescence staining was performed to explore the distributions and cell sources of PDGFB and PDGFD, and to evaluate astrocytic scar, fibrotic scar, inflammatory cells and axon regeneration after SCI. Basso Mouse Scale (BMS) and footprint analysis were performed to evaluate locomotor function recovery after SCI. RESULTS: We found that the expression of PDGFD and PDGFB increased successively after SCI, and PDGFB was mainly secreted by astrocytes, while PDGFD was mainly secreted by macrophages/microglia and fibroblasts. In addition, in situ injection of exogenous PDGFB or PDGFD can lead to fibrosis in the uninjured spinal cord, while this profibrotic effect could be specifically blocked by the PDGFRß inhibitor SU16f. We then treated the mice after SCI with SU16f and found the reduction of fibrotic scar, the interruption of scar boundary and the inhibition of lesion and inflammation, which promoted axon regeneration and locomotor function recovery after SCI. CONCLUSIONS: Our study demonstrates that activation of PDGFRß pathway can directly induce fibrotic scar formation, and specific blocking of this pathway would contribute to the treatment of SCI.

Transcranial direct current stimulation treated by multilead brain reflex instrument accelerates neural functional recovery in a rat model of stroke.

PURPOSE: Clinical research suggests that transcranial direct current stimulation (tDCS) at bilateral supraorbital foramen and inferior orbital rim and nose intersections may facilitate rehabilitation after stroke. However, the underlying neurobiological mechanisms of tDCS remain poorly understood, impeding its clinical application. Here, we investigated the effect of tDCS applied after stroke on neural cells. MATERIALS AND METHODS: Middle cerebral arterial occlusion (MCAO) reperfusion was induced in rats. Animals with comparable infarcts were randomly divided into MCAO group and MCAO + tDCS group. Recovery of neurological function was assessed behaviorally by modified neurological severity score (mNSS). Ischemic tissue damage verified histologically by TTC and HE staining. Immunohistochemical staining, real-time qPCR, and western blot were applied to determine the changes of neural cells in ischemic brains. RESULTS: The results reveal that tDCS treated by multilead brain reflex instrument can promote the recovery of neurological function, remarkably reduce cerebral infarct volume, promote brain tissue rehabilitation, and can effectively inhibit astrocytosis and enhance neuronal survival and synaptic function in ischemic brains. CONCULSIONS: Our study suggests that tDCS treated by multilead brain reflex instrument could be prospectively developed into a clinical treatment modality.

Outcomes of radical debridement versus no debridement for the treatment of thoracic and lumbar spinal tuberculosis.

PURPOSE: Whether radical debridement is necessary for the treatment of thoracic and lumbar tuberculosis is still questionable. The objective of this prospective randomized study was to compare the outcomes of radical debridement versus no debridement for the treatment of thoracic and lumbar tuberculosis. METHODS: Seventy-four thoracic and lumbar tuberculosis patients with a neurological function of grade D and E underwent surgery and received the same chemotherapy regiment from January 2009 to October 2014. All patients were divided into group A and B by taking the drawing of lots. In group A, radical debridement, bone graft, and instrumentation were performed. Isolated posterior instrumentation without debridement were performed in group B. The operative time, blood loss, visual analogue score (VAS), erythrocyte sedimentation rate (ESR), kyphotic angle, Frankel grading, fusion rate, and complications were evaluated. RESULTS: Group B had a better clinical outcome with regard to the operative time, blood loss, VAS score first week post-operatively, and the ESR value in the third and sixth month post-operatively than group A, and the differences between the two groups about those values all presented a significant difference (P < 0.05). However, no difference was observed between the two groups for the kyphotic angle (P = 0.088) and fusion rate (P = 0.164) at the final follow-up. Neurological function of all cases exhibited normal neurological function in the two groups at the final follow-up. Two cases of pulmonary infection and four cases of wound infection in group A. No serious complications were observed in group B. CONCLUSIONS: Isolated posterior instrumentation without debridement is a suitable treatment for selected patients because of minor surgical trauma, fewer complications, and spontaneous fusion.

Comparing the early efficacies of autologous bone grafting and interbody fusion cages for treating degenerative lumbar instability in patients of different ages.

PURPOSE: The aim of this study was to compare the early efficacies of interbody fusion using autologous bone graft or an interbody fusion cage in a modified transforaminal lumbar interbody fusion (TLIF) in patients of different ages with degenerative lumbar instability. METHODS: Data from 33 patients with double-segment degenerative lumbar instability treated with a modified TLIF combined with a posterior fixation system from December 2008 to June 2014 were retrospectively analyzed. The two segments separately received an interbody bone graft fusion and an interbody fusion cage. Patients were divided by age into group A (middle-aged and elderly group, age ≥ 55 years, n = 13) and group B (young adult group, age < 55 years, n = 20). The clinical efficacy of the modified TLIF combined with a posterior fixation system was assessed using the Japanese Orthopaedic Association (JOA), Oswestry Disability Index (ODI), and Visual Analogue Scale (VAS) scores obtained before and after surgery, and at final follow-up. We measured the mean intervertebral space height, intervertebral foramen height, lumbar lordosis angle, and inter-technique differences in the mean intervertebral space height and intervertebral foramen height. Interbody fusion was evaluated using the Suk standard. RESULTS: Patients in group A followed-up for 19.15 ± 8.01 months. Patients in group B followed-up for 14.80 ± 5.47 months. The post-operative JOA, ODI, VAS, and lumbar lordosis angle were improved significantly. Moreover, the early clinical follow-up effect was good. In group A, significant differences in the intervertebral foramen height post-surgery and at final follow-up, and the mean intervertebral space height at final follow-up were noted. The intervertebral foramen and space heights were increased in the interbody cage group. In group B, a significant difference in the intervertebral foramen height at final follow-up was noted. The mean intervertebral space height post-surgery and at final follow-up was significantly increased between the two fusion methods. Bony fusion was achieved in all cases. The fusion time of autologous bone graft and interbody fusion cage was 5.46 ± 1.20 months and 6.77 ± 1.01 months respectively in group A, and 5.50 ± 1.28 months and 6.35 ± 1.76 months respectively in group B, the difference in fusion time between techniques was significant. CONCLUSION: At different ages, the interbody fusion cages can better preserve the intervertebral space and the intervertebral foramen height. However, autologous bone graft can rapidly achieve a bony fusion. Interbody fusion cages are therefore ideal for young adults, while autologous bone grafting is ideal for middle-aged and elderly patients who receive a modified TLIF.

Effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration after spinal cord injury in rats.

[Purpose] The aim of this study was to evaluate the effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration in rats with spinal cord injury. [Subjects and Methods] A rat model of spinal cord injury was constructed by using the Allen weight-drop method. These rats were randomly divided into normal, spinal cord injury, and spinal cord injury + oscillating electrical field stimulation groups. The experimental group received the intervention with oscillating electrical field stimulation, and the control group received the intervention with an electrical field stimulator without oscillating electrical field stimulation. Each group was then randomly divided into seven subgroups according to observation time (1, 2, 4, 6, 8, 10, and 12 weeks). Basso-Beattie-Bresnahan score and inclined plate test score evaluation, motor evoked potential detection, and histological observation were performed. [Results] In the first 2 weeks of oscillating electrical field stimulation, the oscillating electrical field stimulation and inclined plate test scores of spinal cord injury group and spinal cord injury + oscillating electrical field stimulation group were not significantly different. In the fourth week, the scores of the spinal cord injury group were significantly lower than those of the spinal cord injury + oscillating electrical field stimulation group. The motor evoked potential incubation period in the spinal cord injury + oscillating electrical field stimulation group at the various time points was shorter than that in the spinal cord injury group. In the sixth week, the relative area of myelin in the spinal cord injury + oscillating electrical field stimulation group was evidently larger than that in the spinal cord injury group. [Conclusion] Oscillating electrical field stimulation could effectively improve spinal cord conduction function and promote motor function recovery in rats with spinal cord injury, as well as promote myelin regeneration.

Partial tumor resection combined with chemotherapy for multiple myeloma spinal cord compression.

BACKGROUND: Some controversies about the optimal therapy for multiple myeloma (MM) spinal cord compression are still presented. This study was conducted to investigate the efficacy of partial tumor resection combined with chemotherapy for MM spinal cord compression. METHODS: Eleven patients were diagnosed with MM spinal cord compression. Radiological examinations manifested 12 spinal lesions on 11 patients. All patients were treated with partial tumor resection with adjuvant chemotherapy. The mean procedure time, the mean blood loss, visual analog scale score, Oswestry Disability Index (ODI) score, neurological status, complication, recurrence, and quality of life were evaluated. RESULTS: Eleven patients were followed up with a mean of 25.1 months. The mean procedure time was 152.6 ± 30.4 min, and the mean blood loss was 396.4 ± 82.7 ml. Overall pain control rate was 89 %, with complete pain relief in 64 %, and partial pain relief in 25 %. The median pre-ODI values of 85 % significantly improved to 12 % at the last follow-up. Neurological improvement of one to two grades was observed 6 months postoperatively. Complications included pleural effusion, titanium cage loose, and thrombocytopenia in three patients each. Local recurrence was 18.2 %. One patient died of pulmonary infection. Quality of life improved from 39 % before surgery to 81 % in ten survivors at the last follow-up. CONCLUSIONS: Partial tumor resection combined with chemotherapy seems to be an effective treatment for MM spinal cord compression owing to the minor surgical trauma, fewer complications, and effective pain control. Total resection of the tumor is not necessary for MM of the spine.

Safety and efficacy of a new procedure for treating traumatic iliopsoas hematoma: a retroperitoneoscopic approach.

BACKGROUND: Surgical treatment is often recommended for traumatic iliopsoas hematoma. Open surgeries lead to severe surgical trauma, and minimally invasive surgeries cannot completely remove the hematoma. A new treatment protocol for traumatic iliopsoas hematoma by retroperitoneoscopic approach has been introduced. The goal of this study was to determine the safety and efficacy of retroperitoneoscopic approach used to remove iliopsoas hematoma. METHODS: Between January 2009 and July 2012, 13 patients were diagnosed of traumatic iliopsoas hematoma. Retroperitoneoscopic surgeries were performed on all patients to remove the hematomas after admission. The size of hematoma, VASA score and neurologic status were dynamic evaluated before and after surgery. Soft tissue damage and complications caused by retroperitoneoscopic approach also were recorded and evaluated. RESULTS: We performed retroperitoneoscopic surgery to remove traumatic iliopsoas hematoma successfully on 13 patients without complications. The mean procedure time was 52.5 ± 13.4 min, and mean blood loss was 30.7 ± 9.2 ml. Hematoma was completely removed confirmed by ultrasound after surgery. Pain in the affected lower abdominal and thigh immediately was relieved totally for ten patients and partly for three patients after surgery. Quadriceps strength was restored to grade 5 and pain completely disappeared 2 months postoperatively on all patients. Numbness along the femoral nerve distribution disappeared for 11 patients and improved for 2 patients until the last follow-up. None of 13 patients suffered from infection or a new hematoma during follow-up. CONCLUSIONS: Retroperitoneoscopic approach is a safe and effective procedure alternative to conventional surgical approach for treating traumatic iliopsoas hematoma in terms of complete removal of hematoma, minimal invasiveness, absence of radiation, and rapid recovery.

Effect of Myelin Debris on the Phenotypic Transformation of Astrocytes after Spinal Cord Injury in Rats.

After spinal cord injury (SCI), the accumulation of myelin debris can serve as proinflammatory agents, hindering axon regrowth and exacerbating damage. While astrocytes have been implicated in the phagocytosis of myelin debris, the impact of this process on the phenotypic transformation of astrocytes and their characteristics following SCI in rats is not well understood. Here, we demonstrated that the conditioned medium of myelin debris can trigger apoptosis in rat primary astrocytes in vitro. Using a compressional SCI model in rats, we observed that astrocytes can engulf myelin debris through ATP-binding cassette transporter sub-family A member 1 (ABCA1), and these engulfed cells tend to transform into A1 astrocytes, as indicated by C3 expression. At 4 days post-injury (dpi), astrocytes rapidly transitioned into A1 astrocytes and maintained this phenotype from 4 to 28 dpi, while A2 astrocytes, characterized by S100, were only detected at 14 and 28 dpi. Reactive astrocytes, identified by Nestin, emerged at 4 and 7 dpi, whereas scar-forming astrocytes, marked by N-cadherin, were evident at 14 and 28 dpi. This study illustrates the distribution patterns of astrocyte subtypes and the potential interplay between astrocytes and myelin debris after SCI in rats. We emphasize that myelin debris can induce astrocyte apoptosis in vitro and promote the transformation of astrocytes into A1 astrocytes in vivo. These two classification methods are not mutually exclusive, but rather complementary.

hBcl2 overexpression in BMSCs enhances resistance to myelin debris-induced apoptosis and facilitates neuroprotection after spinal cord injury in rats.

After spinal cord injury (SCI), the accumulation of myelin debris at the lesion exacerbates cell death and hinders axonal regeneration. Transplanted bone marrow mesenchymal stem cells (BMSCs) have been proven to be beneficial for SCI repair, but they are susceptible to apoptosis. It remains unclear whether this apoptotic process is influenced by myelin debris. Here, we constructed rat BMSCs overexpressing human B-cell lymphoma 2 (hBcl2) alone (hBcl2 group), BMSCs overexpressing hBcl2 with an endoplasmic reticulum-anchored segment (hBcl2-cb) (cb group), and a negative control group (NC group) for transplantation in this study. Immunocytochemistry staining validated the successful expression of hBcl2 in BMSCs within the hBcl2 group and cb group. All BMSCs from each group exhibited the ability to phagocytize myelin debris. Nevertheless, only BMSCs derived from the hBcl2 group exhibited heightened resistance to apoptosis and maintained prolonged viability for up to 5 days when exposed to myelin debris. Notably, overexpression of hBcl2 protein, rather than its endoplasmic reticulum-anchored counterpart, significantly enhanced the resistance of BMSCs against myelin debris-induced apoptosis. This process appeared to be associated with the efficient degradation of myelin debris through the Lamp1+ lysosomal pathway in the hBcl2 group. In vivo, the hBcl2 group exhibited significantly higher numbers of surviving cells and fewer apoptotic BMSCs compared to the cb and NC groups following transplantation. Furthermore, the hBcl2 group displayed reduced GFAP+ glial scarring and greater preservation of NF200+ axons in the lesions of SCI rats. Our results suggest that myelin debris triggers apoptosis in transplanted BMSCs, potentially elucidating the low survival rate of these cells after SCI. Consequently, the survival rate of transplanted BMSCs is improved by hBcl2 overexpression, leading to enhanced preservation of axons within the injured spinal cord.

Roles of TRPM channels in glioma.

Gliomas are the most common type of primary brain tumor. Despite advances in treatment, it remains one of the most aggressive and deadly tumor of the central nervous system (CNS). Gliomas are characterized by high malignancy, heterogeneity, invasiveness, and high resistance to radiotherapy and chemotherapy. It is urgent to find potential new molecular targets for glioma. The TRPM channels consist of TRPM1-TPRM8 and play a role in many cellular functions, including proliferation, migration, invasion, angiogenesis, etc. More and more studies have shown that TRPM channels can be used as new therapeutic targets for glioma. In this review, we first introduce the structure, activation patterns, and physiological functions of TRPM channels. Additionally, the pathological mechanism of glioma mediated by TRPM2, 3, 7, and 8 and the related signaling pathways are described. Finally, we discuss the therapeutic potential of targeting TRPM for glioma.

•TRPM channels are widely expressed in the human body and play an important role in gliomas.• Abnormal expression of TRPM2, 3, 7, and 8 channels in gliomas is associated with disease severity and prognosis.•TRPM2, 3, 7, and 8 channels are effective targets in glioma.

Construction of a 5-Gene super-enhancer-related signature for osteosarcoma prognosis and the regulatory role of TNFRSF11B in osteosarcoma.

Osteosarcoma, one of the most common primary malignancies in children and adolescents, has the primary characteristics of a poor prognosis and high rate of metastasis. This study used super-enhancer-related genes derived from two different cell lines to construct five novel super-enhancer-related gene prognostic models for patients with osteosarcoma. The training and testing datasets were used to confirm the prognostic models of the five super-enhancer-related genes, which resulted in an impartial predictive element for osteosarcoma. The immunotherapy and prediction of the response to anticancer drugs have shown that the risk signature of the five super-enhancer-related genes positively correlate with chemosensitivity. Furthermore, functional analysis of the risk signature genes revealed a significant relationship between gene groups and the malignant characteristics of tumours. TNF Receptor Superfamily Member 11b (TNFRSF11B) was selected for functional verification. Silencing of TNFRSF11B suppressed the proliferation, migration, and invasion of osteosarcoma cells in vitro and suppressed osteosarcoma growth in vivo. Moreover, transcriptome sequencing was performed on MG-63 cells to study the regulatory mechanism of TNFRSF11B in osteosarcoma cells, and it was discovered that TNFRSF11B is involved in the development of osteosarcoma via the phosphoinositide 3-kinase signalling pathway. Following the identification of TNFRSF11B as a key gene, we selected an inhibitor that specifically targeted this gene and performed molecular docking simulations. In addition, risedronic acid inhibited osteosarcoma growth at both cellular and molecular levels. In conclusion, the super-enhancer-related gene signature is a viable therapeutic tool for osteosarcoma prognosis and treatment.

Super-enhancer-driven LIF promotes the mesenchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia.

BACKGROUND: The mesenchymal (MES) subtype of glioblastoma (GBM) is believed to be influenced by both cancer cell-intrinsic alterations and extrinsic cellular interactions, yet the underlying mechanisms remain unexplored. METHODS: Identification of microglial heterogeneity by bioinformatics analysis. Transwell migration, invasion assays, and tumor models were used to determine gene function and the role of small molecule inhibitors. RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to explore the underlying regulatory mechanisms. RESULTS: We identified the inflammatory microglial subtype of tumor-associated microglia (TAM) and found that its specific gene ITGB2 was highly expressed in TAM of MES GBM tissues. Mechanistically, the activation of ITGB2 in microglia promoted the interaction between the SH2 domain of STAT3 and the cytoplasmic domain of ITGB2, thereby stimulating the JAK1/STAT3/IL-6 signaling feedback to promote the MES transition of GBM cells. Additionally, microglia communicated with GBM cells through the interaction between the receptor ITGB2 on microglia and the ligand ICAM-1 on GBM cells, while an increased secretion of ICAM-1 was induced by the proinflammatory cytokine LIF. Further studies demonstrated that inhibition of CDK7 substantially reduced the recruitment of SNW1 to the super-enhancer of LIF, resulting in transcriptional inhibition of LIF. We identified notoginsenoside R1 as a novel LIF inhibitor that exhibited synergistic effects in combination with temozolomide. CONCLUSIONS: Our research reveals that the epigenetic-mediated interaction of GBM cells with TAM drives the MES transition of GBM and provides a novel therapeutic avenue for patients with MES GBM.

Unilateral biportal endoscopic technique combined with percutaneous transpedicular screw fixation for thoracolumbar burst fractures with neurological symptoms: technical note and preliminary report.

BACKGROUND: Previous studies on thoracolumbar fractures with neurological symptoms have focused on how to achieve satisfactory fracture reduction, adequate nerve decompression, and stable spinal alignment. With the development of the minimally invasive spine surgery technique, achieving satisfactory treatment results and reducing iatrogenic trauma at the same time has become a new goal of spinal surgery. This research used percutaneous transpedicular screw distraction to partially reduce the fractured vertebrae, followed by completing nerve decompression and reducing residual displacement bone fragments with the assistance of the unilateral biportal endoscopic (UBE) technique to achieve full protection of bone-ligament tissue and obtain good clinical efficacy. METHODS: Guide wires were safely inserted into the fractured vertebra and adjacent upper and lower vertebra under the surveillance of anteroposterior and lateral X-ray fluoroscopy. Transpedicular screws were implanted via guide wires on the side with mild neurological deficits or bone fragment compression (the opposite side of the endoscopic operation). A titanium rod was installed and moderately distracted to reduce the fractured vertebra. Then, under the guidance of the endoscopic view, the laminectomy and ligamentum flavum resection were completed according to the position of the protruding bone fragment into the spinal canal, and the compressed dural sac or nerve root was fully exposed and decompressed. An L-shaped replacer was used to reduce residual bone fragments. The ipsilateral transpedicular screws and rod were installed and adjusted to match the contralateral side. The drainage tube was indwelled, and the incision was closed. The preoperative and postoperative images of the patients were evaluated, and the recovery of neurological symptoms was observed. RESULTS: Surgery was successfully completed on all six patients, and no intraoperative conversion to open surgery was performed. Postoperative images showed good reduction of the protruding bone fragment and good placement of all screws. At the last follow-up, the neurological symptoms of all patients returned to normal. CONCLUSION: The UBE technique combined with percutaneous transpedicular screw fixation in the treatment of thoracolumbar fractures with neurological symptoms can effectively achieve the reduction of displaced bone fragments, improve damaged nerve function, stabilize spinal alignment, and protect the integrity of bone-ligament tissue.

PIWI-interacting RNAs: Critical roles and therapeutic targets in cancer.

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a novel class of small regulatory RNAs (approximately 24-31 nucleotides in length) that often bind to members of the PIWI protein family. piRNAs regulate transposons in animal germ cells; piRNAs are also specifically expressed in many human tissues and regulate pivotal signaling pathways. Additionally, the abnormal expression of piRNAs and PIWI proteins has been associated with various malignant tumours, and multiple mechanisms of piRNA-mediated target gene dysregulation are involved in tumourigenesis and progression, suggesting that they have the potential to serve as new biomarkers and therapeutic targets for tumours. However, the functions and potential mechanisms of action of piRNAs in cancer have not yet been elucidated. This review summarises the current findings on the biogenesis, function, and mechanisms of piRNAs and PIWI proteins in cancer. We also discuss the clinical significance of piRNAs as diagnostic or prognostic biomarkers and therapeutic tools for cancer. Finally, we present some critical questions regarding piRNA research that need to be addressed to provide insight into the future development of the field.

Super-enhancers complexes zoom in transcription in cancer.

Super-enhancers (SEs) consist of multiple typical enhancers enriched at high density with transcription factors, histone-modifying enzymes and cofactors. Oncogenic SEs promote tumorigenesis and malignancy by altering protein-coding gene expression and noncoding regulatory element function. Therefore, they play central roles in the treatment of cancer. Here, we review the structural characteristics, organization, identification, and functions of SEs and the underlying molecular mechanism by which SEs drive oncogenic transcription in tumor cells. We then summarize abnormal SE complexes, SE-driven coding genes, and noncoding RNAs involved in tumor development. In summary, we believe that SEs show great potential as biomarkers and therapeutic targets.