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BACKGROUND Pyogenic spondylodiscitis is infection of the intervertebral disc or discs and the adjacent vertebrae. This retrospective study aimed to compare the effectiveness of percutaneous endoscopic lumbar debridement (PELD) versus posterior lumbar interbody fusion (PLIF) in 40 patients with pyogenic spondylodiscitis (PSD). MATERIAL AND METHODS Medical records of patients who underwent PELD (n=18) or PLIF (n=22) for PSD between 2018 and 2023 were reviewed. The recorded outcomes encompassed surgical duration, intraoperative blood loss, Oswestry Disability Index (ODI) measurements, Visual Analog Scale (VAS) assessments, C-reactive protein (CRP) levels, duration of hospitalization, erythrocyte sedimentation rate (ESR), American Spinal Injury Association (ASIA) grading, lumbar sagittal parameters, and the incidence of complications. RESULTS The PELD group had shorter surgical duration, less intraoperative blood loss, and shorter length of hospital stay compared to the PLIF group (P<0.01). At the last follow-up, both groups had significant improvement in ESR, CRP levels, and ASIA classification (P<0.001), but there was no significant difference between the 2 groups (P>0.05). The PELD group had lower ODI and VAS ratings at 1 month and 3 months, respectively (P<0.01). The PLIF group had significant improvements in intervertebral space height and lumbar lordosis angle (P<0.01). CONCLUSIONS Both PLIF and PELD surgical approaches demonstrate adequate clinical efficacy in the treatment of monosegmental PSD. PLIF can better ensure more spinal stability than PELD, but PELD offers advantages such as reduced minimal surgical trauma, shorter operative duration, and faster recovery after surgery.
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Desbridamiento , Discitis , Vértebras Lumbares , Procedimientos Quirúrgicos Mínimamente Invasivos , Fusión Vertebral , Humanos , Masculino , Femenino , Discitis/cirugía , Persona de Mediana Edad , Fusión Vertebral/métodos , Vértebras Lumbares/cirugía , Desbridamiento/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Anciano , Adulto , Endoscopía/métodos , Tiempo de Internación , Tempo OperativoRESUMEN
Staphylococcus aureus (S. aureus) persistence in macrophages, potentially a reservoir for recurrence of chronic osteomyelitis, contributes to resistance and failure in treatment. As the mechanisms underlying survival of S. aureus in macrophages remain largely unknown, there has been no treatment approved. Here, in a mouse model of S. aureus osteomyelitis, we identified significantly up-regulated expression of SLC7A11 in both transcriptomes and translatomes of CD11b+F4/80+ macrophages, and validated a predominant distribution of SLC7A11 in F4/80+ cells around the S. aureus abscess. Importantly, pharmacological inhibition or genetic knockout of SLC7A11 promoted the bactericidal function of macrophages, reduced bacterial burden in the bone and improved bone structure in mice with S. aureus osteomyelitis. Mechanistically, aberrantly expressed SLC7A11 down-regulated the level of intracellular ROS and reduced lipid peroxidation, contributing to the impaired bactericidal function of macrophages. Interestingly, blocking SLC7A11 further activated expression of PD-L1 via the ROS-NF-κB axis, and a combination therapy of targeting both SLC7A11 and PD-L1 significantly enhanced the efficacy of clearing S. aureus in vitro and in vivo. Our findings suggest that targeting both SLC7A11 and PD-L1 is a promising therapeutic approach to reprogram the bactericidal function of macrophages and promote bacterial clearance in S. aureus osteomyelitis.
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Sistema de Transporte de Aminoácidos y+ , Macrófagos , Osteomielitis , Infecciones Estafilocócicas , Animales , Ratones , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Osteomielitis/metabolismo , Osteomielitis/microbiología , Especies Reactivas de Oxígeno/metabolismo , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Staphylococcus aureusRESUMEN
Osteoarthritis (OA) is a prevalent degenerative pathology, however, there exists a lack of cost-effective pharmacological interventions that efficaciously inhibit its progression. ganoderic acid A (GAA), a triterpenoid derived from Ganoderma lucidum, possesses antiapoptotic and -inflammatory effects. Our objective was to better understand the therapeutic effects of GAA on OA as well as to elucidate the underlying mechanisms of its action. To establish an OA cell model in vitro, chondrocytes (CHONs) were treated with interleukin (IL)-1ß. Subsequently, the investigation was conducted afterward according to the following indicators: cell viability, apoptosis, inflammation, and extracellular matrix (ECM) degradation. Western blotting analysis (WB) was employed to assess both endoplasmic reticulum (ER) stress and proteins associated with the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, based on molecular docking studies, GAA exhibits a significant binding competence to p65. OA mouse models were constructed by performing a destabilization medial meniscus (DMM) operation. Moreover, histopathology and immunohistochemistry were used to determine the GAA therapeutic effect in reducing OA in vivo. Our findings revealed that GAA has antiapoptotic, anti-inflammatory, and anti-ECM degradation effects by inhibiting the ER stress and NF-κB axis in CHONs in vitro. Furthermore, our findings suggest that GAA may attenuate the progression of osteoarthritis in vivo. GAA can protect CHONs by regulating apoptosis, ECM changes, and inflammation thereby preventing OA progression. These promising results indicate that GAA may be a therapeutic agent for OA treatment.
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Ácidos Heptanoicos , Lanosterol/análogos & derivados , FN-kappa B , Osteoartritis , Ratones , Animales , FN-kappa B/metabolismo , Simulación del Acoplamiento Molecular , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Condrocitos/metabolismo , Estrés del Retículo Endoplásmico , Interleucina-1beta/metabolismo , Células CultivadasRESUMEN
BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, with poor outcomes for patients with metastatic disease or chemotherapy resistance. Cirsiliol is a recently found flavonoid with anti-tumor effects in various tumors. However, the effects of cirsiliol in the regulation of aggressive behaviors of OS remain unknown. METHODS: The effect of cirsiliol on the proliferation of OS cells was detected using a cell counting kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining, while cell apoptosis was detected using flow cytometry. Immunofluorescence was applied to visualize the expression level of the mitochondria, lysosomes and microtubule-associated protein light chain 3 (LC3). A computational molecular docking technique was used to predict the interaction between cirsiliol and the AKT protein. The impact of cirsiliol on resistance was investigated by comparing it between a methotrexate (MTX)-sensitive OS cell line, U2OS, and a MTX-resistant OS cell line, U2OS/MTX. Finally, in situ xenogeneic tumor models were used to validate the anti-tumor effect of cirsiliol in OS. RESULTS: Cirsiliol inhibited cell proliferation and induced apoptosis in both U2OS and U2OS/MTX300 OS cells. In addition, treatment with cirsiliol resulted in G2 phase arrest in U2OS/MTX300 and U2OS cells. Cell fluorescence probe staining results showed impaired mitochondria and increased autophagy in OS cells after treatment with cirsiliol. Mechanistically, it was found that cirsiliol targeted AKT by reducing the phosphorylation of AKT, which further activated the transcriptional activity of forkhead Box O transcription factor 1 (FOXO1), ultimately affecting the function of OS cells. Moreover, in situ tumorigenesis experiments showed that cirsiliol inhibited the tumorigenesis and progression of OS in vivo. CONCLUSIONS: Cirsiliol inhibits OS cell growth and induces cell apoptosis by reducing AKT phosphorylation and further promotes FOXO1 expression. These phenomena indicate that cirsiliol is a promising treatment option for OS.
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Neoplasias Óseas , Osteosarcoma , Niño , Humanos , Adolescente , Metotrexato/farmacología , Metotrexato/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Apoptosis , Proliferación Celular , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Carcinogénesis , Autofagia , Mitocondrias/metabolismo , Proteína Forkhead Box O1RESUMEN
BACKGROUND Key-hole surgery is a minimally invasive technique that has shown promise in various surgical procedures. This study aimed to assess the clinical effectiveness of preoperative coronal MRI-assisted key-hole surgery for the treatment of patients with cervical spondylotic radiculopathy (CSR). MATERIAL AND METHODS A total of 30 patients diagnosed with CSR and undergoing key-hole surgery with CMRI assistance were included in the study. Various parameters, including surgical segments, incision length, disease duration, operative time, intraoperative fluoroscopy times, intraoperative blood loss, complications, and length of hospitalization, were recorded. Precise measurements of Cobb angles and intervertebral space height were taken before and after the surgical procedure. Surgical outcomes were evaluated using modified Macnab criteria, visual analogue scale (VAS), Japanese Orthopaedic Association Scores (JOA), and neck disability index (NDI). RESULTS The average duration of disease was 6.47±3.29 months, with an average incision length of 1.94±0.15 cm and operative time of 57.83±4.34 minutes. The average intraoperative blood loss was 33.70±9.28 ml, with an average of 3.50±0.73 intraoperative fluoroscopies. The average duration of hospitalization was 4.10±1.27 days. Preoperative and postoperative measurements showed no statistically significant difference in C2-C7 Cobb angles and intervertebral space height. However, there were significant improvements in postoperative VAS, NDI, and JOA scores compared to preoperative scores. The surgical effectiveness rate was 100%, with a high rate of good and excellent outcomes. CONCLUSIONS The findings of this study suggest that preoperative CMRI-assisted key-hole surgery for single-segment CSR is a safe and effective treatment option with low complication rates. The clinical benefits include high security and good outcomes. Further research and larger studies are warranted to validate these findings.
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Radiculopatía , Fusión Vertebral , Espondilosis , Humanos , Radiculopatía/diagnóstico por imagen , Radiculopatía/cirugía , Pérdida de Sangre Quirúrgica , Espondilosis/diagnóstico por imagen , Espondilosis/cirugía , Espondilosis/complicaciones , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Resultado del Tratamiento , Fusión Vertebral/métodos , Imagen por Resonancia Magnética , Estudios Retrospectivos , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugíaRESUMEN
BACKGROUND: Intervertebral disc degeneration (IVDD) is widely recognized as the primary etiological factor underlying low back pain, often necessitating surgical intervention as the sole recourse in severe cases. The metabolic pathway of arachidonic acid (AA), a pivotal regulator of inflammatory responses, influences the development and progression of IVDD. METHODS: Initially, a comparative analysis was conducted to investigate the relationship between AA expression patterns and different stages of IVDD using single-cell sequencing (scRNA-seq) data. Additionally, three machine learning methods (LASSO, random forest, and support vector machine recursive feature elimination) were employed to identify hub genes associated with IVDD. Subsequently, a novel artificial intelligence prediction model was developed for IVDD based on an artificial neural network algorithm and validated using an independent dataset. The identified hub genes were further subjected to functional enrichment, immune infiltration, and Connectivity Map analysis. Moreover, external validation was performed using flow cytometry and real-time reverse transcription polymerase chain reaction analysis. RESULTS: Both scRNA-seq and bulk RNA-seq data revealed a positive correlation between the severity of IVDD and the AA metabolic pathway. They also revealed increased AA metabolic activity in macrophages and neutrophils, as well as enhanced intercellular communication with nucleus pulposus cells. Utilizing advanced machine learning algorithms, five hub genes (AKR1C3, ALOX5, CYP2B6, EPHX2, and PLB1) were identified, and an incipient diagnostic model was developed with an AUC of 0.961 in the training cohort and 0.72 in the validation cohort. An in-depth exploration of the functionality of these hub genes revealed their notable association with inflammatory responses and immune cell infiltration. Lastly, AH6809 was found to delay IVDD by inhibiting AKR1C3. CONCLUSIONS: This study offers comprehensive insights into potential biomarkers and small molecules associated with the early pathogenesis of IVDD. The identified biomarkers and the developed integrated diagnostic model hold great promise in predicting the onset of early IVDD. AH6809 was established as a therapeutic target for AKR1C3 in the treatment of IVDD, as evidenced by computer simulations and biological experiments.
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Inteligencia Artificial , Degeneración del Disco Intervertebral , Humanos , Ácido Araquidónico , Degeneración del Disco Intervertebral/genética , Multiómica , BiomarcadoresRESUMEN
BACKGROUND: Osteosarcoma (OSA) is the most prevalent type of bone cancer with a high rate of metastasis. Circular RNAs (CircRNAs) play an essential role in multiple aspects of tumour biology. This study aimed to elucidate the role of circEMB in OSA. METHODS: circRNAs related to OSA invasion were identified via RNA sequencing and qRT-PCR. The relationship between circEMB levels and clinicopathological features of OSA was examined using the clinical specimens and data of 53 patients with OSA. Several in vivo and in vitro experiments, including intravital imaging, whole-transcriptome sequencing, transwell assay, flow cytometry, dual-luciferase reporter assay, RIP assay, RNA pull-down assay and RNA-FISH, were performed to examine the effects of circEMB on the malignant behaviour of OSA. RESULTS: A novel circRNA, named circEMB (hsa_circ_001310), was identified in this study. circEMB can promote the malignant behaviour of OSA. In vitro experiments revealed that circEMB knockdown decreased cell proliferation, inhibited tumour invasion and metastasis; increased apoptosis and resulted in G1/S phase arrest. In vivo experiments revealed that circEMB knockdown inhibited tumour growth and metastasis in xenograft-bearing mice. Mechanistically, circEMB affects the malignant behaviour of OSA by mediating EGFR as an miR-3184-5p sponge. In addition, the circEMB/miR-3184-5p/EGFR axis modulates methotrexate (MTX) resistance in OSA. CONCLUSIONS: CircEMB plays a critical role in promoting cancer via the miR-3184-5p/EGFR pathway, indicating that circEMB may serve as a therapeutic target for OSA.
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Spinal cord injury (SCI) is a serious disorder of the central nervous system with a high disability rate. Long noncoding RNAs (lncRNAs) are reported to mediate many biological processes. The aim of this study was to explore lncRNA and mRNA expression profiles and functional networks after SCI. Differentially expressed genes between SCI model rats and sham controls were identified by microarray assays and analyzed by functional enrichment. Key lncRNAs were identified using a support vector machine- (SVM-) recursive feature elimination (RFE) algorithm. A trans and cis regulation model was used to analyze the regulatory relationships between lncRNAs and their targets. An lncRNA-related ceRNA network was established. We identified 5465 differentially expressed lncRNAs (DE lncRNAs) and 8366 differentially expressed mRNAs (DE mRNAs) in the SCI group compared with the sham group (fold change > 2.0, p < 0.05). Four genes were confirmed by qRT-PCR which were consistent with the microarray data. GSEA analysis showed that most marked changes occurred in pathways related to immune inflammation and nerve cell function, including cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and GABAergic synapse. Enrichment analysis identified 30 signaling pathways, including those associated with immune inflammation response. A total of 40 key lncRNAs were identified using the SVM-RFE algorithm. A key lncRNA-mRNAs coexpression network was generated for 230 951 lncRNA-mRNA pairs with half showing positive correlations. Several key DE lncRNAs were predicted to have "cis"- or "trans"-regulated target genes. The transcription factors, Sp1, JUN, and SOX10, may regulate the interaction between XR_001837123.1 and ETS 1. In addition, five pairs of ceRNA regulatory sequences were constructed. Many mRNAs and lncRNAs were found to be dysregulated after SCI. Bioinformatic analysis showed that DE lncRNAs may play crucial roles in SCI. It is anticipated that these findings will provide new insights into the underlying mechanisms and potential therapeutic targets for SCI.
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ARN Largo no Codificante , ARN Mensajero , Traumatismos de la Médula Espinal , Animales , Ratas , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Inflamación , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismoRESUMEN
Objectives: Osteosarcoma is a malignant bone tumor with poor outcomes affecting the adolescents and elderly. In this study, we comprehensively assessed the metabolic characteristics of osteosarcoma patients and constructed a hexosamine biosynthesis pathway (HBP)-based risk score model to predict the prognosis and tumor immune infiltration in patients with osteosarcoma. Methods: Gene expression matrices of osteosarcoma were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. GSVA and univariate Cox regression analysis were performed to screen the metabolic features associated with prognoses. LASSO regression analysis was conducted to construct the metabolism-related risk model. Differentially expressed genes (DEGs) were identified and enrichment analysis was performed based on the risk model. CIBERSORT and ESTIMATE algorithms were executed to evaluate the characteristics of tumor immune infiltration. Comparative analyses for immune checkpoints were performed and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict immunotherapeutic response. Finally, hub genes with good prognostic value were comprehensive analyzed including drug sensitivity screening and immunohistochemistry (IHC) experiments. Results: Through GSVA and survival analysis, the HBP pathway was identified as the significant prognostic related metabolism feature. Five genes in the HBP pathway including GPI, PGM3, UAP1, OGT and MGEA5 were used to construct the HBP-related risk model. Subsequent DEGs and enrichment analyses showed a strong correlation with immunity. Further, CIBERSORT and ESTIMATE algorithms showed differential immune infiltration characteristics correlated with the HBP-related risk model. TIDE algorithms and immune checkpoint analyses suggested poor immunotherapeutic responses with low expression of immune checkpoints in the high-risk group. Further analysis revealed that the UAP1 gene can predict metastasis. IHC experiments suggested that UAP1 expression correlated significantly with the prognosis and metastasis of osteosarcoma patients. When screening for drug sensitivity, high UAP1 expression was suggestive of great sensitivity to antineoplastic drugs including cobimetinib and selumetinib. Conclusion: We constructed an HBP-related gene signature containing five key genes (GPI, PGM3, UAP1, OGT, MGEA5) which showed a remarkable prognostic value for predicting prognosis and can guide immunotherapy and targeted therapy for osteosarcoma.
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Neoplasias Óseas , Osteosarcoma , Adolescente , Humanos , Anciano , Hexosaminas , Osteosarcoma/patología , Pronóstico , Neoplasias Óseas/genética , Análisis de SupervivenciaRESUMEN
The osteosarcoma (OS) microenvironment is composed of tumor cells, immune cells, and stromal tissue and is emerging as a pivotal player in OS development and progression. Thus, microenvironment-targeted strategies are urgently needed to improve OS treatment outcomes. Using principal component analysis (PCA), we systematically examined the tumor microenvironment (TME) and immune cell infiltration of 88 OS cases and constructed a TME scoring system based on the TMEscore high and TMEscore low phenotypes. Our analysis revealed that TMEscore high correlates with longer survival in OS patients, elevated immune cell infiltration, increased immune checkpoints, and increased sensitivity to chemotherapy. TMEscore low strongly correlated with immune exclusion. These observations were externally validated using a GEO dataset (GSE21257) from 53 OS patients. Our laboratory data also proved our findings. This finding enhances our understanding of the immunological landscape in OS and may uncover novel targeted therapeutic strategies.
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Neoplasias Óseas , Osteosarcoma , Neoplasias Óseas/genética , Neoplasias Óseas/terapia , Humanos , Factores Inmunológicos , Inmunoterapia , Osteosarcoma/genética , Osteosarcoma/terapia , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
Objectives: We aimed to examine whether metformin (MET) use is associated with a reduced risk of total knee arthroplasty (TKA) and low severity of knee pain in patients with knee osteoarthritis (OA) and diabetes and/or obesity. Methods: Participants diagnosed with knee OA and diabetes and/or obesity from June 2000 to July 2019 were selected from the information system of a local hospital. Regular MET users were defined as those with recorded prescriptions of MET or self-reported regular MET use for at least 6 months. TKA information was extracted from patients' surgical records. Knee pain was assessed using the numeric rating scale. Log-binomial regression, linear regression, and propensity score weighting (PSW) were performed for statistical analyses. Results: A total of 862 participants were included in the analyses. After excluding missing data, there were 346 MET non-users and 362 MET users. MET use was significantly associated with a reduced risk of TKA (prevalence ratio: 0.26, 95% CI: 0.15 to 0.45, p < 0.001), after adjustment for age, gender, body mass index, various analgesics, and insurance status. MET use was significantly associated with a reduced degree of knee pain after being adjusted for the above covariates (ß: −0.48, 95% CI: −0.91 to −0.05, p = 0.029). There was a significantly accumulative effect of MET use on the reduced risk of TKA. Conclusion: MET can be a potential therapeutic option for OA. Further clinical trials are needed to determine if MET can reduce the risk of TKA and the severity of knee pain in metabolic-associated OA patients.
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Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Accumulating evidence has revealed that microRNAs (miRNAs) play a crucial role in the progression of OS. In this study, we found that miR-744-5p was the least expressed miRNA in patients with OS by analyzing GSE65071 from the GENE EXPRESSION OMNIBUS (GEO) database. Through real-time quantitative PCR (qRT-PCR), western blotting, colony formation assay, 5-Ethynyl-2-Deoxyuridine (EdU) incorporation assay, transwell migration, and invasion assays, we demonstrated its ability to inhibit the proliferation, migration, and invasion of OS cells in vitro. According to the luciferase reporter assay, transforming growth factor-ß1 (TGFB1) was negatively regulated by miR-744-5p and reversed the effects of miR-744-5p on OS. Subcutaneous tumor-forming animal models and tail vein injection lung metastatic models were used in animal experiments, and it was found that miR-744-5p negatively regulated tumor growth and metastasis in vivo. Furthermore, rescue assays verified that miR-744-5p regulates TGFB1 expression in OS. Further experiments revealed that the p38 MAPK signaling pathway is involved in the miR-744-5p/TGFB1 axis. Generally, this study suggests that miR-744-5p is a negative regulator of TGFB1 and suppresses OS progression and metastasis via the p38 MAPK signaling pathway.
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Neoplasias Óseas , MicroARNs , Osteosarcoma , Adolescente , Animales , Neoplasias Óseas/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Osteosarcoma/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factores de Crecimiento Transformadores , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND: Circular RNAs (circRNAs) are involved in diverse processes that drive cancer development. However, the expression landscape and mechanistic function of circRNAs in osteosarcoma (OS) remain to be studied. METHODS: Bioinformatic analysis and high-throughput RNA sequencing tools were employed to identify differentially expressed circRNAs between OS and adjacent noncancerous tissues. The expression level of circ_001422 in clinical specimens and cell lines was measured using qRT-PCR. The association of circ_001422 expression with the clinicopathologic features of 55 recruited patients with OS was analyzed. Loss- and gain-of-function experiments were conducted to explore the role of circ_001422 in OS cells. RNA immunoprecipitation, fluorescence in situ hybridization, bioinformatics database analysis, RNA pulldown assays, dual-luciferase reporter assays, mRNA sequencing, and rescue experiments were conducted to decipher the competitive endogenous RNA regulatory network controlled by circ_001422. RESULTS: We characterized a novel and abundant circRNA, circ_001422, that promoted OS progression. Circ_001422 expression was dramatically increased in OS cell lines and tissues compared with noncancerous samples. Higher circ_001422 expression correlated with more advanced clinical stage, larger tumor size, higher incidence of distant metastases and poorer overall survival in OS patients. Circ_001422 knockdown markedly repressed the proliferation and metastasis and promoted the apoptosis of OS cells in vivo and in vitro, whereas circ_001422 overexpression exerted the opposite effects. Mechanistically, competitive interactions between circ_001422 and miR-195-5p elevated FGF2 expression while also initiating PI3K/Akt signaling. These events enhanced the malignant characteristics of OS cells. CONCLUSIONS: Circ_001422 accelerates OS tumorigenesis and metastasis by modulating the miR-195-5p/FGF2/PI3K/Akt axis, implying that circ_001422 can be therapeutically targeted to treat OS.
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MicroARNs/metabolismo , Osteosarcoma/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Circular/genética , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Metástasis de la Neoplasia , Osteosarcoma/patologíaRESUMEN
Deficits in intrinsic neuronal capacities in the spinal cord, a lack of growth support, and suppression of axonal outgrowth by inhibitory molecules mean that spinal cord injury almost always has devastating consequences. As such, one of the primary targets for the treatment of spinal cord injury is to develop strategies to antagonize extrinsic or intrinsic axonal growth-inhibitory factors or enhance the factors that support axonal growth. Among these factors, a series of individual protein level disorders have been identified during the generation of axons following spinal cord injury. Moreover, an increasing number of studies have indicated that post-translational modifications of these proteins have important implications for axonal growth. Some researchers have discovered a variety of post-translational modifications after spinal cord injury, such as tyrosination, acetylation, and phosphorylation. In this review, we reviewed the post-translational modifications for axonal growth, functional recovery, and neuropathic pain after spinal cord injury, a better understanding of which may elucidate the dynamic change of spinal cord injury-related molecules and facilitate the development of a new therapeutic strategy for spinal cord injury.
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Osteosarcoma (OS) often occurs in children and often undergoes metastasis, resulting in lower survival rates. Information on the complexity and pathogenic mechanism of OS is limited, and thus, the development of treatments involving alternative molecular and genetic targets is hampered. We categorized transcriptome data into metastasis and nonmetastasis groups, and 400 differential RNAs (230 messenger RNAs (mRNAs) and 170 long noncoding RNAs (lncRNAs)) were obtained by the edgeR package. Prognostic genes were identified by performing univariate Cox regression analysis and the Kaplan-Meier (KM) survival analysis. We then examined the correlation between the expression level of prognostic lncRNAs and mRNAs. Furthermore, microRNAs (miRNAs) corresponding to the coexpression of lncRNA-mRNA was predicted, which was used to construct a competitive endogenous RNA (ceRNA) regulatory network. Finally, multivariate Cox proportional risk regression analysis was used to identify hub prognostic genes. Three hub prognostic genes (ABCG8, LOXL4, and PDE1B) were identified as potential prognostic biomarkers and therapeutic targets for OS. Furthermore, transcriptions factors (TFs) (DBP, ESX1, FOS, FOXI1, MEF2C, NFE2, and OTX2) and lncRNAs (RP11-357H14.16, RP11-284N8.3, and RP11-629G13.1) that were able to affect the expression levels of genes before and after transcription were found to regulate the prognostic hub genes. In addition, we identified drugs related to the prognostic hub genes, which may have potential clinical applications. Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) confirmed that the expression levels of ABCG8, LOXL4, and PDE1B coincided with the results of bioinformatics analysis. Moreover, the relationship between the hub prognostic gene expression and patient prognosis was also validated. Our study elucidated the roles of three novel prognostic biomarkers in the pathogenesis of OS as well as presenting a potential clinical treatment for OS.
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Osteosarcoma is the most common primary malignancy of the bones, and is associated with a high rate of metastasis and a poor prognosis. A tight association between the tumor microenvironment (TME) and osteosarcoma metastasis has been established. In the present study, the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm was applied to calculate the immune and stromal scores of patients with osteosarcoma based on data from The Cancer Genome Atlas database. A metagene approach and deconvolution method were used to reveal distinct TME landscapes in patients with osteosarcoma. Bioinformatics analysis was used to identify differentially expressed genes (DEGs) associated with metastasis and immune infiltration in osteosarcoma, and a risk model was constructed using the DEGs with potential prognostic significance. Subsequently, gene set enrichment and Spearman's correlation analyses were used to delineate the biological processes associated with these prognostic biomarkers. Finally, immunohistochemical (IHC) analysis was performed to evaluate the expression levels of immune infiltrates and prognostic biomarkers in clinical osteosarcoma tissues. The results of the ESTIMATE demonstrated that patients with non-metastatic osteosarcoma presented with higher immune/stromal scores and a more favorable prognosis compared with those with metastatic osteosarcoma. The TME landscapes in patients with osteosarcoma suggested that high levels of tumor-infiltrating immune cells (TIICs) may suppress metastasis. Increased numbers of CD56bright natural killer cells, immature B cells, M1 macrophages and neutrophils, and lower levels of M2 macrophages were observed in the non-metastatic tissues compared with those in the metastatic tissues. A total of 69 DEGs were identified to be associated with metastasis and immune infiltration in osteosarcoma. Of these, GATA3, LPAR5, EVI2B, RIAM and CFH exhibited prognostic potential and were highly expressed in non-metastatic osteosarcoma tissues based on the IHC analysis results. These biomarkers were involved in various immune-related biological processes and were positively associated with multiple TIICs and immune signatures. The risk model constructed using these prognostic biomarkers demonstrated high predictive accuracy for the prognosis of osteosarcoma. In conclusion, the present study proposed a five-biomarker prognostic signature for the prediction of metastasis and immune infiltration in patients with osteosarcoma.