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The remarkable application of tin oxide in various domains is indebted to its photoelectronic merits. However, significant efforts to discover its photocatalytic potential were restricted through arduous challenges, which were the amelioration of light-harvesting and -utilizing. In fact, the uncommon light absorption energy has drawn veil over the brilliance of astounding oxidation potential, which is much more than that of TiO2. Herein, our attention was focused on the taking advantages of self-template structure for simultaneously enjoying the two sides of photoelectronic justification as well as the S-step system for eminent charge dissociation. In this regard, the optimized Cu-modified SnO2 yolk-shell ((5)YS-CuSnO) spheres were engineered through the copper modulation into glycerate-assisted metal-organic structure. As a result, the exceptional light-harvesting was achieved through desirable defects and oxygen vacancy resulted from Cu-doping, and also efficient light-utilization was obtained by the multi-scattering/reflection effect resulted from multi-shell configuration. After the effectual incorporation (40 wtâ) of (5)YS-CuSnO was encapsulated into the V2O5-decorated wrinkled g-C3N4 lamella (VO-WCN), the dual S-step VO-WCN@(5)YS-CuSnO introduced unprecedented levofloxacin (LFC) decontamination performance, which was kinetically 5.2 and 30.2-times greater than of the (5)YS-CuSnO and bare SnO2 yolk-shell. The conspicuous fulfillment of nanocomposite was manifested in the LFC mineralization, pharmaceutical effluent treatment within 360 min, and successive cycling reactions. The fusion of the extraordinary architecture of YS-CuSnO with S-Step system not only initiates the facile and practical photocatalytic exploitation, but shade light on some undeveloped side of tin oxide.
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Antibacterianos , Cobre , Fotólise , Compostos de Estanho , Compostos de Estanho/química , Cobre/química , Antibacterianos/química , Compostos de Nitrogênio/química , GrafiteRESUMO
BACKGROUND: Deep venous thrombosis (DVT) after spinal surgery has recently attracted increasing attention. Patients with spinal metastases who undergo decompression with fixation are at a high risk of developing DVT. D-dimer levels indicate the risk of DVT, and the purpose of our study was to investigate D-dimer levels as a predictor of DVT perioperatively. METHODS: We prospectively evaluated 100 patients with spinal metastases. D-dimer tests were performed twice: once before surgery and one day postoperatively. DVT was diagnosed by duplex ultrasonographic assessment of both lower extremities. Pulmonary embolisms (PEs) were diagnosed using multidetector computed tomography and pulmonary angiography. Perioperative serum D-dimer levels were compared between the DVT (+) and DVT (-) groups. The cutoff value of the D-dimer level was calculated using receiver operating characteristic analysis. RESULTS: Preoperative and postoperative DVT prevalences were 8.0% (8/100) and 6.6% (6/91), respectively, and none of the patients developed PE. Before surgery, there was no significant differences in D-dimer levels between the pre-DVT (+) and pre-DVT (-) groups. After surgery, the D-dimer level one-day postoperatively for the post-DVT (+) group (17.6 ± 11.8 mg/L) was significantly higher than that of the post-DVT (-) group (5.0 ± 4.7 mg/L). The cutoff value of the postoperative D-dimer level was 9.51(mg/L), and the sensitivity and specificity for the optimum threshold were 83.3% and 89.4%, respectively. CONCLUSIONS: Our findings suggest that preoperative D-dimer level may not be a predictor of DVT. Preoperative ultrasound examinations should be routinely performed in patients with spinal metastases. Postoperative D-dimer levels greater than 9.51(mg/L) are a predictive factor for the early diagnosis of DVT after spine surgery. TRIAL REGISTRATION: Our study was registered on Chinese Clinical Trial Registry (No.ChiCTR2000029737). Registered 11 February 2020 - Retrospectively registered, https://www.chictr.org.cn/index.aspx.
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Descompressão Cirúrgica , Produtos de Degradação da Fibrina e do Fibrinogênio , Neoplasias da Coluna Vertebral , Trombose Venosa , Humanos , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Feminino , Masculino , Trombose Venosa/sangue , Trombose Venosa/etiologia , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/epidemiologia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Descompressão Cirúrgica/efeitos adversos , Neoplasias da Coluna Vertebral/cirurgia , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/sangue , Adulto , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Embolia Pulmonar/sangue , Embolia Pulmonar/etiologia , Embolia Pulmonar/diagnóstico , Valor Preditivo dos Testes , Biomarcadores/sangueRESUMO
Spinal metastasis (SM) frequently occurs in renal cell carcinoma (RCC) patients. Our preliminary work showed that CX3CL1 plays a positive role in SM. The objective of the present study was to verify whether CX3CL1 activates the downstream pathway by binding to CX3CR1 in RCC cells, ultimately promoting RCC to metastasize to the spine. The expression of CX3CL1 and CX3CR1 in tissue samples was detected by immunohistochemistry and western blotting. ELISA was used to quantify the concentration of CX3CL1 in the serum. The expression level of CX3CR1 in RCC cell lines was also detected. The CellTiter-Glo assay and flow cytometry were used to analyze cell viability and apoptosis of RCC cells. Transwell and wound healing assay were used to analyze the effect of CX3CL1 on the invasion and migration ability of RCC cells. Specific inhibitors were used to interfere with key molecules in the signaling pathway to further explore the signal transduction in RCC cells after CX3CL1 stimulation. The expression of CX3CR1 in SM from RCC was higher than that in limb bone metastases. Among the five RCC cell lines, 786O cells expressed the highest level of CX3CR1. CX3CL1 neither inhibited the proliferation of 786O cells nor promoted the apoptosis of 786O cells. However, it promoted the migration and invasion of RCC cells. After CX3CL1 stimulation, Src and Focal adhesion kinase (FAK) phosphorylation levels increased in RCC cells. Bosutinib and PF-00562271 inhibited Src/FAK phosphorylation and cell motility and invasion triggered by CX3CL1 stimulation. CX3CL1 in the red bone marrow of spinal cancellous bone enhances migration and invasion abilities of RCC cells, thereby promoting RCC metastasize to the spine. The migration and invasion of RCC cells activated by CX3CL1 are at least partially dependent on Src/FAK activation.
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Carcinoma de Células Renais , Quimiocina CX3CL1 , Neoplasias Renais , Neoplasias da Coluna Vertebral , Medula Óssea , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular , Quimiocina CX3CL1/genética , Humanos , Neoplasias Renais/patologia , Transdução de Sinais , Neoplasias da Coluna Vertebral/secundárioRESUMO
Our present study investigated whether exosome secretion of nucleus pulposus cells (NPCs) is regulated by autophagy. Different autophagic states of NPCs were induced by rapamycin (Rap), bafilomycin A1 (Baf) and other agents, and it was found that exosomes were secreted in an autophagy-dependent manner. Activation or inhibition of autophagy increased or decreased, respectively, the amount of exosomes that were released into the extracellular space. In addition, in order to confirm that Rap-promoted release of exosomes was mediated by autophagy rather than other pathways, we used autophagy associated gene 5 (ATG5) small-interfering RNA (siRNA) to silence the expression of ATG5 gene, which is indispensable for autophagy. The results showed that siRNA against ATG5 (siATG5) induced an accumulation of intraluminal vesicles (ILVs) in NPCs and a concomitant decrease in the amount of exosomes isolated from supernatant. Ras homolog gene (Rho) and Rho-associated coiled-coil forming protein kinase (ROCK) family molecules are capable of cytoskeletal remodeling and affecting vesicle transport. Therefore, we carried out targeted interventions and evaluated the effects of the RhoC/ROCK2 pathway on the secretion of exosomes within autophagic environment. Knockdown of RhoC and ROCK2 with corresponding siRNA significantly inhibited the secretion of exosomes originating from ILVs in NPCs, even when NPCs were subsequently treated with Rap. Taken together, our findings suggest that autophagy positively regulates expression levels of RhoC and ROCK2, and that the RhoC/ROCK2 pathway exerts a key function on NPCs-derived exosome secretion.
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Autofagia/fisiologia , Exossomos/metabolismo , Núcleo Pulposo/metabolismo , Proteína de Ligação a GTP rhoC/genética , Animais , Secreções Corporais/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Quinases Associadas a rho/metabolismo , Proteína de Ligação a GTP rhoC/metabolismoRESUMO
The clinical treatment of metastatic spinal tumor remains a huge challenge owing to the intrinsic limitations of the existing methods. Programmed cell death protein 1 (PD1)/programmed cell death ligand 1 (PD-L1) pathway blockade has been explored as a promising immunotherapeutic strategy; however, their inhibition has a low response rate, leading to the minimal cytotoxic T cell infiltration. To ameliorate the immunosuppressive microenvironment of intractable tumor and further boost the efficacy of immunotherapy, we report an all-round mesoporous nanocarrier composed of an upconverting nanoparticle core and a large-pore mesoporous silica shell (UCMS) that is simultaneously loaded with photosensitizer molecules, the IDO-derived peptide vaccine AL-9, and PD-L1 inhibitor. The IDO-derived peptide can be recognized by the dendritic cells and presented to CD8+ cytotoxic T cells, thereby enhancing the immune response and promoting the killing of the IDO-expressed tumor cells. Meanwhile, the near-infrared (NIR) activated photodynamic therapy (PDT) could induce immunogenic cell death (ICD), which promotes the effector T-cell infiltration. By combining the PDT-elicited ICD, peptide vaccine and immune checkpoint blockade, the designed UCMS@Pep-aPDL1 successfully potentiated local and systemic antitumor immunity and reduced the progression of metastatic foci, demonstrating a synergistic strategy for cancer immunotherapy.
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Inibidores de Checkpoint Imunológico/farmacologia , Morte Celular Imunogênica/efeitos dos fármacos , Imunoterapia/métodos , Metástase Neoplásica/tratamento farmacológico , Vacinas de Subunidades Antigênicas/farmacologia , Animais , Antígeno B7-H1/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Citocinas , Feminino , Inibidores de Checkpoint Imunológico/química , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Coluna Vertebral , Vacinas de Subunidades Antigênicas/químicaRESUMO
INTRODUCTION: Middle- and long-term outcomes of multi-segmental lumbar spinal stenosis treated with Dynesys stabilization (DS) have rarely been reported. Older age and multi-segmental degeneration may be positive factors in achieving satisfactory outcomes following DS. The present study aimed to compare the middle- and long-term outcomes of DS with lumbar fusion for treatment of multi-segmental lumbar spinal stenosis (ms-LSS) in elderly patients. MATERIALS AND METHODS: This study retrospectively analyzed patients with ms-LSS treated by DS or lumbar fusion from January 2011 to April 2013. Twenty-two patients were included in the Dynesys group, and 44 patients treated by lumbar fusion and rigid fixation were included in the fusion group. Clinical outcomes were assessed by VAS and ODI. Radiological outcomes were measured by range of motion (ROM) of stabilized segments and the proximal adjacent segment, intervertebral disc height (DH) and L1-S1 lumbar lordosis angle (LL). Modified Pfirrmann grade score was used to access disc degeneration. OUTCOMES: The mean follow-up time of the Dynesys group and fusion group was 68.50 ± 6.40 and 70.14 ± 7.26 months, respectively. Baseline data were similar between the two groups. There were no significant differences between the two groups in terms of improvement of clinical outcomes (VAS and ODI). DS preserved a certain degree of ROM (3.74 ± 2.00) of surgical segments. ROM of proximal adjacent segment underwent an increase in both groups at the final follow-up. The DH of the surgical segments and proximal adjacent segment in both groups was significantly lower than that before surgery (P = 0.000). LL of both groups improved (P = 0.000), and there was no significant difference between the two groups. The modified Pfirrmann score of proximal adjacent segment of both groups increased at the final follow-up. The fusion group underwent a more significant increase (P = 0.000), whereas the inter-group difference showed no significance (P = 0.090). CONCLUSION: DS is a safe and effective surgical treatment of multi-segmental lumbar spinal stenosis in the elderly population. DS preserves a certain degree of mobility of surgical segments.
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Artrodese/métodos , Vértebras Lombares/cirurgia , Estenose Espinal/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Lordose/etiologia , Masculino , Pessoa de Meia-Idade , Radiografia , Amplitude de Movimento Articular , Estudos Retrospectivos , Fusão Vertebral/métodosRESUMO
This cross-sectional study aimed to identify gender differences in the cervical postures when young adults were using mobile phones, as well as the correlations between the postures and the digital devices use (computer and mobile phone). Questionnaires regarding the habits of computer and mobile phone use were administrated to 429 subjects aged from 17 to 33 years old (19.75 ± 2.58 years old). Subjects were instructed to stand habitually and use a mobile phone as in daily life; the sagittal head and cervical postures were measured by head flexion, neck flexion angle and gaze angle. Male participants had a significantly larger head flexion angle (96.41° ± 12.23° vs. 93.57° ± 12.62°, p = 0.018) and neck flexion angle (51.92° ± 9.55° vs. 47.09° ± 9.45°, p < 0.001) than females. There were significant differences in head (F = 3.62, p = 0.014) and neck flexion (F = 3.99, p = 0.009) between different amounts of computer use. Practitioner Summary: We investigated possible gender differences in head and neck postures of young adults using mobile phones, as well as the potential correlations between these postures and digital device use. We found that males displayed larger head and neck flexion angles than females, which were associated with the amount of computer use.
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Computadores/estatística & dados numéricos , Pescoço , Postura , Smartphone/estatística & dados numéricos , Adolescente , Adulto , Telefone Celular/estatística & dados numéricos , Computadores de Mão/estatística & dados numéricos , Estudos Transversais , Feminino , Humanos , Masculino , Amplitude de Movimento Articular , Fatores Sexuais , Coluna Vertebral , Adulto JovemRESUMO
Surgery remains the standard treatment for spinal metastasis. However, uncontrolled intraoperative bleeding poses a significant challenge for adequate surgical resection and compromises surgical outcomes. In this study, we develop a thrombin (Thr)-loaded nanorobot-hydrogel hybrid superstructure by incorporating nanorobots into regenerated silk fibroin nanofibril hydrogels. This superstructure with superior thixotropic properties is injected percutaneously and dispersed into the spinal metastasis of hepatocellular carcinoma (HCC) with easy bleeding characteristics, before spinal surgery in a mouse model. Under near-infrared irradiation, the self-motile nanorobots penetrate into the deep spinal tumor, releasing Thr in a controlled manner. Thr-induced thrombosis effectively blocks the tumor vasculature and reduces bleeding, inhibiting tumor growth and postoperative recurrence with Au nanorod-mediated photothermal therapy. Our minimally invasive treatment platform provides a novel preoperative therapeutic strategy for HCC spinal metastasis effectively controlling intraoperative bleeding and tumor growth, with potentially reduced surgical complications and enhanced operative outcomes.
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Background: Annexin A9 (ANXA9) has been proved to be concerned with cancer development. However, to explore the clinical consequences of ANXA9 in lung adenocarcinoma (LUAD), especially its correlation to spinal metastasis (SM) has no in-depth study. The study was expected to elucidate the mechanism of ANXA9 in regulating SM of LUAD and create a productive nano-composites delivery system targeting this gene for treatment of SM. Methods: Harmine (HM), a ß-carboline extracted from the traditional Chinese herb Peganum harmala, loaded Au@MSNs@PEG@Asp6 (NPS) nano-composites were synthesized. Bioinformatics analysis and clinical specimens' tests were used to verify the association between ANXA9 and prognosis of LUAD with SM. The immunohistochemistry (IHC) was employed to detect the expression levels of the ANXA9 protein in LUAD tissues with or without SM, and its significance in clinic was also explored. ANXA9siRNA was applied to investigate the molecular mechanism of ANXA9 in tumor behaviors. The HM release kinetics was detected by high performance liquid chromatography (HPLC) method. The cellular uptake efficiency of nanoparticles by A549 cells was observed by fluorescence microscope. Antitumor effects of nanoparticles were assessed in the nude mouse model of SM. Results: The genomic amplification of ANXA9 was prevalent in LUAD tissues and closely associated with poor outcome and SM (P<0.01). The experimental result manifested that high expression of ANXA9 could lead to wretched prognosis and ANXA9 was an independent risk factor for survival (P<0.05). After impeding expression of ANXA9, the proliferation and metastatic ability of tumor cells obviously decreased, and expression of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9) were considerably downregulated, while the expression of associated oncogene pathway were downregulated (P<0.01) as well. The synthesized HM-loaded NPS nano-composites could target to cancer and response to reactive oxygen species (ROS) to release HM slowly. Notably, in comparison to free HM, the nano-composites showed excellent targeting and anti-tumor effects in the A549 cell-bearing mouse model. Conclusions: ANXA9 may serve as a novel biomarker for predicting poor prognosis in LUAD, and we provided an efficient and targeting drug delivery nano-composites system for precise treatment of SM from LUAD.
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Introduction: Bone is a common metastatic site for small cell lung cancer (SCLC). Bone metastasis (BM) in patients have are known to show poor prognostic outcomes. We explored the epidemiological characteristics of BM in SCLC patients and create a new deep learning model to predict outcomes for cancer-specific survival (CSS) and overall survival (OS). Materials and Methods: Data for SCLC patients diagnosed with or without BM from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox proportional hazards regression models were used to evaluate the effects of prognostic variables on OS and CSS. Through integration of these variables, nomograms were created for the prediction of CSS and OS rates at 3-month,6- month,and 12-month. Harrell's coordination index, calibration curves,and time- dependent ROC curves were used to assess the nomograms' accuracy. Decision tree analysis was used to evaluate the clinical application value of the established nomogram. Results: In this study, 4201 patients were enrolled. Male sex, tumor size 25 but <10, brain and liver metastases, as well as chemotherapy were associated with a high risk for BM. Tumor size, Age, N stage, gender, liver metastasis, radiotherapy as well as chemotherapy were shown to be prognostic variables for OS, and the prognostic variables for CSS were added to the tumor number in addition. Based on these results, nomograms for CSS and OS were established separately. Internal as well as external validation showed that the C-index, calibration cuurve and DCA had good constructive correction effect and clinical application value. Decision tree analysis further confirmed the prognostic factors of OS and CSS. Discussion: The nomogram and decision tree models developed in this study effectively guided treatment decisions for SCLC patients with BM. The creation of prediction models for BM SCLC patients may be facilitated by deep learning models.
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The bone matrix has distinct architecture and biochemistry which present a barrier to synthesizing bone-mimetic regenerative scaffolds. To mimic the natural structures and components of bone, biomimetic structural decellularized extracellular matrix (ECM)/regenerated silk fibroin (RSF) scaffolds incorporated with magnetic nanoparticles (MNP) are prepared using a facile synthetic methodology. The ECM/RSF/MNP scaffold is a hierarchically organized and interconnected porous structure with silk fibroin twined on the collagen nanofibers. The scaffold demonstrates saturation magnetization due to the presence of MNP, along with good cytocompatibility. Moreover, the ß-sheet crystalline domain of RSF and the chelated MNP could mimic the deposition of hydroxyapatite and enhance compressive modulus of the scaffold by ≈20%. The results indicate that an external static magnetic field (SMF) with a magnetic responsive scaffold effectively promotes cell migration, osteogenic differentiation, neogenesis of endotheliocytes in vitro, and new bone formation in a critical-size femur defect rat model. RNA sequencing reveals that the molecular mechanisms underlying this osteogenic effect involve calsequestrin-2-mediated Ca2+ release from the endoplasmic reticulum to activate Ca2+ /calmodulin/calmodulin-dependent kinase II signaling axis. Collectively, bionic magnetic scaffolds with SMF stimulation provide a potent strategy for bone regeneration through internal structural cues, biochemical composition, and external physical stimulation on intracellular Ca2+ homeostasis.
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Fibroínas , Alicerces Teciduais , Ratos , Animais , Alicerces Teciduais/química , Fibroínas/química , Osteogênese , Cálcio , Biomimética , Calmodulina , Regeneração Óssea/fisiologia , Fenômenos Magnéticos , Engenharia Tecidual/métodosRESUMO
Background: Follicular dendritic cell sarcoma (FDCS) is a rare type of intermediate grade tumor. Mediastinal FDCS with spinal invasion has not been well described. The treatment options include surgical resection and radiation therapy. The body gamma knife is a stereotactic body radiotherapy (SBRT) technology that is widely used in China. The pathological evaluation of a bone lesion after a body gamma knife procedure has not been reported. Here, we report a case of a patient with FDCS with thoracic spine invasion and iliac metastasis treated with surgery and body gamma knife. Case summary: A 36-year-old male patient was hospitalized at Zhongshan Hospital, Fudan University, due to a gradually aggravated pain on the lateral side of the left scapula for 6 months. Imaging examination showed neoplastic lesions on the left side of C7-T2 invading the vertebral body of T1, T2, and caput costae of the second rib and suspected metastasis in the left ilium. FDCS was diagnosed after performing a computed tomography (CT)-guided core needle biopsy, and the thoracic lesion was surgically resected. The body gamma knife was used as an adjuvant radiotherapy for the thoracic lesion and a primary therapy for the left ilium lesion. Iliac bone lesion resection was performed at Zhongshan Hospital, Fudan University, 10 weeks after RT. Compared with the biopsy report, the body gamma knife treatment resulted in a pathological complete response (PCR). The magnetic resonance imaging (MRI) examinations showed stable disease of the thoracic lesion after body gamma knife radiosurgery. Conclusion: This case report describes the treatment of mediastinal FDCS with thoracic spinal invasion and iliac metastasis. The promising outcome suggests that separation surgery is an effective treatment option for mediastinal FDCS with spinal column invasion. It also demonstrates the application prospects of the body gamma knife treatment in malignant lesions of the axial bones.
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Estrogen receptorpositive (ER+) breast cancer (BC) is a malignancy that is prone to metastasis to the spine, which is difficult to treat and often results in poor prognosis. However, the mechanism underlying the tumorigenesis and spinal metastasis of ER+ BC remains unclear. Lysosomal protein transmembrane 5 (LAPTM5) has been reported as a tumor suppressor in several types of cancer, but its role in ER+ BC has not been described. Here, by analyzing a gene sequencing dataset and ER+ BC tissues, tumoradjacent normal tissues and spinal metastatic tissues from patients and mouse models, we found that LAPTM5 expression is negatively related to the progression and spinal metastasis of ER+ BC. Subsequently, in vitro experiments demonstrated that downregulation of LAPTM5 expression promoted the proliferation, migration, and chemoresistance of ER+ BC cells by activating glutaminedependent mTOR signaling. A high level of CX3CL1 could inhibit LAPTM5 expression, explaining how ER+ BC metastasized to the spine. Thus, we found that LAPTM5 functions as a tumor suppressor in ER+ BC and that the CX3CL/CX3CR1/LAPTM5/glutamine axis mediates the spinal metastasis of ER+ BC. This axis may be a promising therapeutic target for ER+ BC.
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Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Membrana/genética , Neoplasias da Mama/patologia , Regulação para Baixo/genética , Feminino , Genes Supressores de Tumor , Humanos , Transdução de SinaisRESUMO
OBJECTIVE: To undertake a systematic review and meta-analysis to evaluate the prognostic value of Forkhead box F2 (FOXF2) levels in different types of cancers prone to bone metastasis. METHODS: A systematic search of publications listed in electronic databases (The Web of Science, EMBASE®, PubMed®, PMC, Science Direct and CNKI) from inception to 5 November 2020 was conducted. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the relationship between FOXF2 levels and patient prognosis including overall survival (OS) and disease-free survival (DFS). RESULTS: Sixteen studies enrolling 8461 participants were included in the meta-analysis. High levels of FOXF2 were a predictor of OS (HR: 0.66; 95% CI 0.51, 0.86) and DFS (HR: 0.60; 95% CI 0.48, 0.76). The trim-and-fill analysis, sensitivity analysis and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. CONCLUSION: These current findings indicate that high FOXF2 levels could be an indicator of a good prognosis in cancer patients with tumours that are prone to bone metastasis. FOXF2 levels might be a clinically important prognostic biomarker.
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Neoplasias Ósseas , Neoplasias , Biomarcadores , Neoplasias Ósseas/genética , Intervalo Livre de Doença , Fatores de Transcrição Forkhead/genética , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Metastatic tumors present great challenges in diagnosis and treatment. Herein, a proof-of-concept theranostic nanoplatform composed of an Au nanoparticle core and a double-shell of metal-organic framework (MOF) and mesoporous silica (MS) is developed for combating spinal metastasis of lung cancer in an orthotopic model. Two drugs, Alpelisib (BYL719) as an inhibitor and cisplatin as a chemotherapeutic drug, are separately loaded into the double-shell with high loading content. A targeting peptide called dYNH and indocyanine green (ICG) are conjugated onto the outmost MS layer for specifically targeting metastatic tumor cells and enhancing photothermal effect. The resultant Au@MOF@MS-ICG -dYNH-PAA (AMMD) shows enhanced cellular uptake on tumor cells and accumulation at metastatic spinal tumors, as evidenced by fluorescent and photoacoustic imaging. Benefiting from this ultra-high affinity to tumor cells and the photothermal effect of ICG, the dual-drug-loaded AMMD (BCAMMD) modified with ICG exhibits superior therapeutic efficacy on spinal tumors. More importantly, bone destruction, which frequently occurs in bone-related tumors, is effectively suppressed by BYL719 in BCAMMD. Hence, by rationally integrating multiple functions, including excellent targeting ability, dual-drug loading, photothermal therapy, and photoacoustic imaging, the developed all-in-one theranostic nanoplatform provides a useful paradigm of employing nanomedicine to treat metastatic spinal tumors efficiently.
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Nanopartículas Metálicas , Nanopartículas , Neoplasias da Coluna Vertebral , Linhagem Celular Tumoral , Ouro , Humanos , Verde de Indocianina , Peptídeos , Fototerapia , Medicina de Precisão , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/terapia , Nanomedicina TeranósticaRESUMO
Objective: Lung cancer patients exhibit spinal metastases from a specific population, and with this study, we aimed to develop a model that can predict this particular group's survival. Methods: Data were retrospectively collected from 83 lung cancer patients who underwent spinal metastasis surgery at our center from 2009 to 2021. After the initial assessment of treatment and scoring effects, a nomogram for survival prediction was created by identifying and integrating critical prognostic factors, followed by a consistency index (C-index) to measure consistency, and finally, a subject working characteristic curve (ROC) to compare the predictive accuracy of the three existing models. Results: The mean postoperative survival was 14.7 months. Surgical treatment significantly improved the VAS and Frankel scores in lung cancer patients with spinal metastases. The revised Tokuhashi score underestimated the life expectancy of these patients. Six independent prognostic factors, including age, extraspinal bone metastasis foci, visceral metastasis, Frankel score, targeted therapy, and radiotherapy, were identified and incorporated into the model. Calibration curves for 3-, 6-, and 12-month overall survival showed a good concordance between predicted and actual risk. The nomogram C-index for the cohort study was 0.800 (95% confidence interval [CI]: 0.757-0.843). Model comparisons showed that the nomogram's prediction accuracy was better than revised Tokuhashi and Bauer's scoring systems. Conclusions: Spine surgery offered patients the possibility of regaining neurological function. Having identified shortcomings in existing scoring systems, we have recreated and validated a new nomogram that can be used to predict survival outcomes in patients with spinal metastases from lung cancer, thereby assisting spinal surgeons in making surgical decisions and personalizing treatment for these patients.
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Although autophagy may be beneficial for maintaining the metabolic balance of the extracellular matrix (ECM) in the nucleus pulposus (NP) and its vitality under inflammation, the underlying mechanism still remains unclear. A previous study found that autophagy activation stimulated the release of exosomes in normal chondrocytes, which are located in a similar avascular environment and share many common features with those of nucleus pulposus cells (NPCs). This study explored the protective effect on matrix degradation in the NP by exosomes derived from autophagy-activated NPCs and exosomal microRNAs. NPCs-derived exosomes (NPCs-Exos) were isolated from culture medium of either normal NPCs or rapamycin-treated NPCs and quantified by nanoparticle tracking analysis. The effect of rapamycin-treated NPC-derived exosomes on NPCs were assessed by coculture with interleukin 1ß (IL-1ß)-stimulated NPCs. After examination of six major proteinases of the ECM, matrix metalloproteinase 13 (MMP-13) was chosen for further study. miR-27a, which targets MMP-13, was investigated through previous studies and bioinformatics tool. The levels of miR-27a were upregulated in both rapamycin-treated NPCs and their exosomes, compared to the control. When exosomal miR-27a was transferred into NPCs, it alleviated IL-1ß-induced degradation of the NPC ECM by targeting MMP-13. Autophagy activation may promote the release of NPCs-derived exosomes and thereby prevent the NPC matrix from degradation. Autophagy activation also alleviates intervertebral disc degeneration (IDD), at least partly via exosomal miR-27a, which restrains MMP-13 expression under IL-1ß stimulation. Our work elucidates a new mechanism for how autophagy may participate in preventing IDD, which may be a promising therapeutic strategy.
Assuntos
Degeneração do Disco Intervertebral , MicroRNAs , Núcleo Pulposo , Autofagia , Células Cultivadas , Matriz Extracelular/metabolismo , Humanos , Degeneração do Disco Intervertebral/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , MicroRNAs/metabolismo , Núcleo Pulposo/metabolismo , Sirolimo/farmacologiaRESUMO
Rationale: The spine is one of the most common metastatic sites of non-small cell lung cancer (NSCLC), and NSCLC spinal metastasis results in serious consequences. Metastatic extravasation of disseminated cancer cells including increased invasiveness, adhesion and transendothelial migration is crucial for tumor metastasis. This study aimed to investigate the mechanisms underlying NSCLC spinal metastasis based on the C-X3-C motif chemokine ligand 1- (CX3CL1) and intercellular adhesion molecule-1- (ICAM-1) mediated signaling network. Methods: Immunohistochemistry, western blotting, and reverse transcription-quantitative PCR were conducted to detect the distribution of CX3CL1/ICAM-1 in different organs. Transwell, adhesion, and transendothelial migration assays were performed to evaluate the regulatory effects of CX3CL1/ICAM-1 on NSCLC cell invasion, adhesion, and transendothelial migration in vitro. A spontaneous spinal metastasis mouse model was established via injection of NSCLC cells into the left cardiac ventricle of NOD/SCID mice. The effects of CX3CL1/ICAM-1 on NSCLC spinal metastasis in vivo were validated using bioluminescent, micro-computerized tomography, immunohistochemistry and histological analyses. Results: CX3CL1 expression was specifically higher in vertebral bone compared with limb bones and lung tissue, and was associated with NSCLC spinal metastasis. Mechanically, vertebral bone marrow endothelial cells (VBMECs) enhanced NSCLC cell invasion via CX3CL1 signaling-mediated activation of the PI3K/AKT pathway. Furthermore, we found that VBMECs effectively induced ICAM-1-dependent NSCLC cell adhesion in coordination with platelets through the CX3CL1/ICAM-1/LFA-1 pathway. Meanwhile, CX3CL1 enhanced NSCLC cell transendothelial migration by increasing permeability of VBMECs via ICAM-1-dependent activation of the Src/GEF-H1 pathway. Interestingly, NSCLC cells were indicated to promote CX3CL1 secretion of VBMECs through MAPK14/ADMA17-dependent CX3CL1 release and NF-κB-dependent CX3CL1 synthesis. Based on these findings, we revealed a novel feedback cycle between circulating NSCLC cells and VBMECs mediated by CX3CL1/ICAM-1 signaling. Further disengagement of the CX3CL1/ICAM-1-mediated feedback cycle in vivo significantly restricted metastasis and prolonged mouse survival. Conclusions: Our results indicated a unique feedback cycle between circulating NSCLC cells and VBMECs mediated by CX3CL1/ICAM-1 signaling, which is necessary for NSCLC spinal metastasis. This work provides a new perspective for underlying the mechanisms of NSCLC spinal metastasis and indicates potential novel targets for the prevention of NSCLC spinal metastasis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quimiocina CX3CL1/metabolismo , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias da Coluna Vertebral/metabolismo , Coluna Vertebral/metabolismo , Células A549 , Idoso , Células da Medula Óssea , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Humanos , Neoplasias Pulmonares/patologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias da Coluna Vertebral/secundário , Migração Transendotelial e TransepitelialRESUMO
BACKGROUND: Long non-coding RNAs (lncRNAs) play important roles in tumor metastasis. The aim of the present study was to investigate their expression profile and potential functions in spinal metastasis (SM) of lung adenocarcinoma. METHODS: We conducted lncRNA and mRNA expression in lung adenocarcinoma and its SM tissue using microarray analysis. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) revealed 10 differentially expressed lncRNAs. Gene ontology and pathway analysis were performed to test the gene effect. Possible target genes of lncRNAs were predicted based on precise algorithms. RESULTS: Microarray analysis found many significantly differentially expressed lncRNAs and mRNAs in lung adenocarcinoma compared with SM. qRT-PCR results aligned with those of the microarray analysis. The expression level of 10 lncRNAs showed the same trend (P<0.05). Biologic pathways known to be involved in cancer were identified among the differentially expressed mRNAs; these include cell adhesion molecules (related to 42 genes), focal adhesion (related to 31 genes), cytokine-cytokine receptor interaction (related to 48 genes), and extracellular matrix-receptor interaction (related to 23 genes). About 9,458 lncRNAs were found to have cis- or trans-genes. A total of 2,317 cis target genes were discovered to be abnormally expressed and could be regulated by lncRNAs in SM of lung adenocarcinoma. CONCLUSIONS: Our results offer a genome-wide differential expression of lncRNA in lung adenocarcinoma and SM, as well as laying the foundation for further investigations of lncRNAs correlated with lung adenocarcinoma metastasis.
RESUMO
Spinal metastasis occurs in 5075% of bone metastases caused by hepatocellular carcinoma (HCC), and HCCderived spinal metastasis can lead to a less favorable prognosis. Recently, several studies have demonstrated that CX3C motif chemokine ligand 1 (CX3CL1) is closely associated with cancer metastasis, and its secretion is modulated by a disintegrin and metalloproteinase 17 (ADAM17). Bone marrow endothelial cells (BMECs) are an essential component of bone marrow. However, little is known about the roles in and effects of BMECs on HCC spinal metastasis. The present study demonstrated that CX3CL1 and CXC motif chemokine receptor 3 (CXCR3) expression was upregulated in HCC spinal metastases, and that CX3CL1 promoted the migration and invasion of HCC cells to the spine. Western blot analysis revealed that the Src/protein tyrosine kinase 2 (PTK2) axis participated in CX3CL1induced HCC cell invasion and migration. CX3CL1 also increased the expression of M2 macrophage markers in THP1 monocytes. BMECs promoted the migration and invasion of Hep3B and MHCC97H cells by secreting soluble CX3CL1, whereas the neutralization of CX3CL1 inhibited this enhancement. CX3CL1 enhanced the activation of the phosphatidylinositol4,5bisphosphate 3kinase catalytic subunit alpha (PIK3CA)/AKT serine/threonine kinase 1 (AKT1) and Ras homolog family member A (RHOA)/Rho associated coiledcoil containing protein kinase 2 (ROCK2) signaling pathways through the Src/PTK2 signaling pathway. Furthermore, ADAM17 was activated by mitogenactivated protein kinase (MAPK)z14 in BMECs and significantly promoted the secretion of CX3CL1. HCC cells enhanced the recruitment and proliferation of BMECs. The overexpression of CX3CR1 facilitated the spinal metastasis of HCC in a mouse model in vivo. In addition, in vivo experiments revealed that BMECs promoted the growth of HCC in the spine. The present study demonstrated that CX3CL1 participates in HCC spinal metastasis, and that BMECs play an important role in the regulation of CX3CL1 in the spinal metastatic environment.