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BACKGROUND: Rheumatoid arthritis (RA) is a multifactorial systemic autoimmune disease characterized by ongoing synovial inflammation, leading to the degradation of cartilage. Cuproptosis, as a newly characterized form of cell death, may influence RA progression by regulating immune cells and chondrocytes. This study sets out to identify the hub cuproptosis-related gene (CRG) associated with the pathogenesis of RA. METHODS: A series of bioinformatic analyses were performed to evaluate the expression score of CRGs and the immune infiltration landscape between RA and normal samples. The hub gene was screened through the correlation analysis of CRGs, and the interaction network between the hub gene and transcription factors (TFs) was constructed. Finally, the hub gene was validated through quantitative real-time polymerase chain reaction (qRT-PCR) of patient samples and cell experiments. RESULTS: Drolipoamide S-acetyltransferase (DLAT) was screened as the hub gene. Correlation analysis between the hub gene and immune microenvironment demonstrated that DLAT had the highest correlation with T follicular helper cells. Eight pairs of DLAT-TF interaction networks were constructed. Single-cell sequencing showed that CRGs were highly expressed in RA chondrocytes, and chondrocytes could be classified into three different subsets. qRT-PCR was used to validate the above results. Dlat knockdown in immortalized human chondrocytes led to significantly improved mitochondrial membrane potentials and reduced levels of intracellular reactive oxygen species (ROS), mitochondrial ROS and apoptosis. CONCLUSIONS: This study rudimentarily demonstrates the correlation between CRGs and immune cell infiltration in RA. The biomarker DLAT may provide comprehensive insights into the pathogenesis and drug targets of RA.
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Apoptose , Artrite Reumatoide , Humanos , Acetiltransferases , Artrite Reumatoide/genética , Condrócitos , Inflamação , Estudos Prospectivos , Espécies Reativas de Oxigênio , CobreRESUMO
PURPOSE: To verify that lateral trochlear inclination (LTI) measured by the transepicondylar axis can reliably be used to evaluate trochlear dysplasia (TD) on MRI and can serve as an objective indication of trochleoplasty for patients with lateral patellar dislocation (LPD). METHODS: Eighty patients with recurrent LPD and eighty healthy subjects were included. TD, posterior condylar angle (PCA), and LTI measured by the posterior condylar reference line (LTIp), surgical transepicondylar axis (LTIs), and anatomical transepicondylar axis (LTIa) were assessed on MRI. The intraclass correlation coefficient (ICC) and Bland-Altman analysis were performed, the correlations and differences amongst the parameters were identified, and a binary logistic regression model was established. RESULTS: Each measurement had excellent inter- and intra-observer agreement. The LTIp, LTIs and LTIa were smaller in the study group than in the control group, with mean differences of 9.0°, 7.2° and 7.0°, respectively (P < 0.001). The PCA was larger in patients with LPD than in the control group (P < 0.001). LTIp was associated with PCA in the study group (r = - 0.41, P < 0.001). The pathological values of LTIp, LTIs and LTIa were 11.7°, 15.3° and 17.4°, respectively. LTIs and LTIa were independent risk factors for LPD, with ORs of 7.33 (95% CI [1.06-52.90], P = 0.048) and 10.29 (95% CI [1.38-76.96], P = 0.023), respectively. CONCLUSION: The LTI can be reliably measured by MRI, but LTIp could potentially decrease the recorded value from the actual inclination angle. LTIs and LTIa are more appropriate to serve as trochleoplasty indications for patients with LPD, which could help orthopedists with surgical decision-making. LEVEL OF EVIDENCE: Level III.
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Instabilidade Articular , Luxação Patelar , Articulação Patelofemoral , Humanos , Luxação Patelar/diagnóstico por imagem , Luxação Patelar/cirurgia , Luxação Patelar/etiologia , Osso e Ossos , Imageamento por Ressonância Magnética , Fatores de Risco , Modelos Logísticos , Instabilidade Articular/cirurgia , Articulação Patelofemoral/diagnóstico por imagem , Articulação Patelofemoral/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: Lactic acid, previously regarded only as an endpoint of glycolysis, has emerged as a major regulator of tumor invasion, growth, and the tumor microenvironment. In this study, we aimed to explore the reprogramming of lactic acid metabolism relevant to osteosarcoma (OS) microenvironment by decoding the underlying lactic acid metabolic landscape of OS cells and intercellular signaling alterations. METHODS: The landscape of OS metabolism was evaluated using single-cell gene expression data, lactic acid metabolism clustering, and screening of the hub genes in lactic acid metabolism of OS samples using transcriptome data. The role of the hub gene NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 6 (NDUFAF6) was validated with in vitro studies and patient experiments. RESULTS: Single-cell RNA sequencing data validated a lactic acid metabolismhigh subcluster in OS. Further investigation of intercellular communications revealed a unique metabolic communication pattern between the lactic acid metabolismhigh subcluster and other subclusters. Next, two lactic acid metabolic reprogramming phenotypes were defined, and six lactic acid metabolism-related genes (LRGs), including the biomarker NDUFAF6, were screened in OS. In vitro studies and patient experiments confirmed that NDUFAF6 is a crucial lactic acid metabolism-associated gene in OS. CONCLUSIONS: The patterns of lactic acid metabolism in OS suggested metabolic reprogramming phenotypes relevant to the tumor microenvironment (TME) and identified NDUFAF6 as an LRG prognostic biomarker.
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Neoplasias Ósseas , Osteossarcoma , Humanos , Ácido Láctico/metabolismo , Glicólise/genética , Osteossarcoma/metabolismo , Neoplasias Ósseas/metabolismo , Biomarcadores/metabolismo , Microambiente Tumoral/genéticaRESUMO
Epigenetic changes are important considerations for degenerative diseases. DNA methylation regulates crucial genes by epigenetic mechanism, impacting cell function and fate. DNA presents hypermethylation in degenerated nucleus pulposus (NP) tissue, but its role in intervertebral disc degeneration (IVDD) remains elusive. This study aimed to demonstrate that methyltransferase mediated hypermethylation was responsible for IVDD by integrative bioinformatics and experimental verification. Methyltransferase DNMT3B was highly expressed in severely degenerated NP tissue (involving human and rats) and in-vitro degenerated human NP cells (NPCs). Bioinformatics elucidated that hypermethylated genes were enriched in oxidative stress and ferroptosis, and the ferroptosis suppressor gene SLC40A1 was identified with lower expression and higher methylation in severely degenerated human NP tissue. Cell culture using human NPCs showed that DNMT3B induced ferroptosis and oxidative stress in NPCs by downregulating SLC40A1, promoting a degenerative cell phenotype. An in-vivo rat IVDD model showed that DNA methyltransferase inhibitor 5-AZA alleviated puncture-induced IVDD. Taken together, DNA methyltransferase DNMT3B aggravates ferroptosis and oxidative stress in NPCs via regulating SLC40A1. Epigenetic mechanism within DNA methylation is a promising therapeutic biomarker for IVDD.
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DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , DNA Metiltransferase 3B , Ferroptose , Degeneração do Disco Intervertebral , Núcleo Pulposo , Estresse Oxidativo , Adulto , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Azacitidina/farmacologia , Modelos Animais de Doenças , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Epigênese Genética , Ferroptose/genética , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Ratos Sprague-Dawley , Regulação para CimaRESUMO
Osteosarcoma (OS) is a type of tumor. Osteosarcoma stem cells (OSCs) are responsible for drug resistance, recurrence, and immunosuppression in OS. We aimed to determine the heterogeneity of OSCs and the immunosuppression mechanisms underlying the interactions between OSCs and tumor-associated macrophages (TAMs). The cell components, trajectory changes, and cell communication profiles of OS cells were analyzed by transcriptomics at the single-cell level. The intercellular communication patterns of OSCs were verified, and the role of the cell hub genes was revealed. Hub geneS are genes that play important roles in regulating certain biological processes; they are often defined as the genes with the strongest regulatory effect on differentially expressed gene sets. Moreover, various cellular components of the OS microenvironment were identified. Malignant cells were grouped, and OSCs were identified. Further regrouping and communication analysis revealed that the genes in the stemness maintenance and differentiation subgroups were involved in communication with macrophages. Key receptor-ligand pairs and target gene sets for cell communication were obtained. Transcriptome data analysis revealed the key gene RARRES2, which is involved in intercellular communication between OSCs and TAMs. In vitro studies confirmed that macrophages promote RARRES2-mediated stemness maintenance in OSCs via the TAM-secreted cytokine insulin-like growth factor 1. Patient studies confirmed that RARRES2 could be a biomarker of OS. OSCs are highly heterogeneous, and different subgroups are responsible for proliferation and communication with other cells. The IGF-RARRES2 axis plays a key role in maintaining OSC stemness through communication with TAMs.
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Neoplasias Ósseas , Osteossarcoma , Humanos , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/metabolismo , Osteossarcoma/patologia , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/metabolismoRESUMO
Zinc (Zn) is a bioabsorbable metal that shows great potential as an implant material for orthopedic applications. Suitable concentrations of zinc ions promote osteogenesis, while excess zinc ions cause apoptosis. As a result, the conflicting impacts of Zn2+ concentration on osteogenesis could prove to be significant problems for the creation of novel materials. This study thoroughly examined the cell viability, proliferation, and osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) cultured in various concentrations of Zn2+ in vitro and validated the osteogenesis effects of zinc implantation in vivo. The effective promotion of cell survival, proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cell (BMSCs) may be achieved at a low concentration of Zn2+ (125 µM). The excessively high concentration of zinc ions (>250 µM) not only reduces BMSCs' viability and proliferation but also causes them to suffer apoptosis due to the disturbed zinc homeostasis and excessive Zn2+. Moreover, transcriptome sequencing was used to examine the underlying mechanisms of zinc-induced osteogenic differentiation with particular attention paid to the PI3K-AKT and TGF-ß pathways. The present investigation elucidated the dual impacts of Zn2+ microenvironments on the osteogenic characteristics of rBMSCs and the associated processes and might offer significant insights for refining the blueprint for zinc-based biomaterials.
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Osteosarcoma (OS) is the most common malignant bone tumor with high pathological heterogeneity. Our study aimed to investigate disulfidptosis-related modification patterns in OS and their relationship with survival outcomes in patients with OS. We analyzed the single-cell-level expression profiles of disulfidptosis-related genes (DSRGs) in both OS microenvironment and OS subclusters, and HMGB1 was found to be crucial for intercellular regulation of OS disulfidptosis. Next, we explored the molecular clusters of OS based on DSRGs and related immune cell infiltration using transcriptome data. Subsequently, the hub genes of disulfidptosis in OS were screened by applying multiple machine models. In vitro and patient experiments validated our results. Three main disulfidptosis-related molecular clusters were defined in OS, and immune infiltration analysis suggested high immune heterogeneity between distinct clusters. The in vitro experiment confirmed decreased cell viability of OS after ACTB silencing and higher expression of ACTB in patients with lower immune scores. Our study systematically revealed the underlying relationship between disulfidptosis and OS at the single-cell level, identified disulfidptosis-related subtypes, and revealed the potential role of ACTB expression in OS disulfidptosis.
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Neoplasias Ósseas , Regulação Neoplásica da Expressão Gênica , Osteossarcoma , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Humanos , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/mortalidade , Osteossarcoma/metabolismo , Microambiente Tumoral/genética , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Actinas/metabolismo , Actinas/genéticaRESUMO
An interbody fusion cage (Cage) is crucial in spinal decompression and fusion procedures for restoring normal vertebral curvature and rebuilding spinal stability. Currently, these Cages suffer from issues related to mismatched elastic modulus and insufficient bone integration capability. Therefore, a gel-casting technique is utilized to fabricate a biomimetic porous titanium alloy material from Ti6Al4V powder. The biomimetic porous Ti6Al4V is compared with polyetheretherketone (PEEK) and 3D-printed Ti6Al4V materials and their respective Cages. Systematic validation is performed through mechanical testing, in vitro cell, in vivo rabbit bone defect implantation, and ovine anterior cervical discectomy and fusion experiments to evaluate the mechanical and biological performance of the materials. Although all three materials demonstrate good biocompatibility and osseointegration properties, the biomimetic porous Ti6Al4V, with its excellent mechanical properties and a structure closely resembling bone trabecular tissue, exhibited superior bone ingrowth and osseointegration performance. Compared to the PEEK and 3D-printed Ti6Al4V Cages, the biomimetic porous Ti6Al4V Cage outperforms in terms of intervertebral fusion performance, achieving excellent intervertebral fusion without the need for bone grafting, thereby enhancing cervical vertebra stability. This biomimetic porous Ti6Al4V Cage offers cost-effectiveness, presenting significant potential for clinical applications in spinal surgery.
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Background: Rheumatoid arthritis (RA) is a disabling autoimmune disease that affects multiple joints. Accumulating evidence suggests that imbalances in liquid-liquid phase separation (LLPS) can lead to altered spatiotemporal coordination of biomolecular condensates, which play important roles in carcinogenesis and inflammatory diseases. However, the role of LLPS in the development and progression of RA remains unclear. Methods: We screened RA and normal samples from GSE12021, GSE55235, and GSE55457 transcriptome datasets and GSE129087 and GSE109449 single-cell sequencing datasets from Gene Expression Omnibus database to investigate the pathogenesis of LLPS-related hub genes at the transcriptome and single cell sequencing levels. Machine learning algorithms and weighted gene co-expression network analysis were applied to screen hub genes, and hub genes were validated using correlation studies. Results: Differential analysis showed that 36 LLPS-related genes were significantly differentially expressed in RA, further random forest and support vector machine identified four and six LLPS-related genes, respectively, and weighted gene co-expression network analysis identified 396 modular genes. Hybridization of the three sets revealed two hub genes, MYC and MAP1LC3B, with AUCs of 0.907 and 0.911, respectively. Further ROC analysis of the hub genes in the GSE55457 dataset showed that the AUCs of MYC and MAP1LC3B were 0.815 and 0.785, respectively. qRT-PCR showed that the expression of MYC and MAP1LC3B in RA synovial tissues was significantly lower than that in the normal control synovial tissues. Correlation analysis between hub genes and the immune microenvironment and single-cell sequencing analysis revealed that both MYC and MAP1LC3B were significantly correlated with the degree of infiltration of various innate and acquired immune cells. Conclusion: Our study reveals a possible mechanism for LLPS in RA pathogenesis and suggests that MYC and MAP1LC3B may be potential novel molecular markers for RA with immunological significance.
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The ideal skull defect repairing material should have good biocompatibility and mechanical properties, and contribute to osteogenesis. In this study, we designed and fabricated biodegradable, bioactive and mechanically robust porous scaffolds composed completely of biological materials. We used a gelatin-chitosan blend as the matrix, sodium phytate instead of toxic glutaraldehyde for cross-linking, and the pH-neutral bioactive glass (PSC) to improve biological activity and mechanical properties. The chitosan-gelatin-30%PSC/sodium phytate composite scaffold avoided the problems of high toxicity in conventional cross-linking agents with glutaraldehyde, the poor mechanical support of the pure chitosan or gelatin scaffold, and the mismatch of the degradation rate with bone repair, becoming a promising new candidate for skull defect repair.
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Quitosana , Alicerces Teciduais , Gelatina , Ácido Fítico , Glutaral , Crânio , Concentração de Íons de HidrogênioRESUMO
The significance of N6-methyladenosine (m6A) RNA modifications in the progression of breast cancer (BC) has been recognised. However, their potential role and mechanism of action in the tumour microenvironment (TME) and immune response has not been demonstrated. Thus, the role of m6A regulators and their downstream target gene components in BC remain to be explored. In this study, we used a series of bioinformatics methods and experiments to conduct exploratory research on the possible role of m6A regulators in BC. First, two regulatory modes of immune activation and inactivation were determined by tumour classification. The TME, immune cell infiltration, and gene set variation analysis results confirmed the reliability of this pattern. The prognostic model of the m6A regulator was established by the least absolute shrinkage and selection operator and univariate and multivariate Cox analyses, with the two regulators most closely related to survival verified by real-time quantitative reverse transcription polymerase chain reaction. Next, the prognostic m6A regulator identified in the model was crossed with the differential copy number of variant genes in invasive BC (IBC), and it was determined that YTHDF1 was a hub regulator. Subsequently, single-cell analysis revealed the expression patterns of m6A regulators in different IBC cell populations and found that YTHDF1 had significantly higher expression in immune-related IBC cells. Therefore, we selected the intersection of the BC differential expression gene set and the differential expression gene set of a cell line with knocked-down YTHDF1 in literature to identify downstream target genes of YTHDF1, in which we found IFI6, EIR, and SPTBN1. A polymerase chain reaction was conducted to verify the results. Finally, we confirmed the role of YTHDF1 as a potential prognostic biomarker through pan-cancer analysis. Furthermore, our findings revealed that YTHDF1 can serve as a new molecular marker for BC immunotherapy.
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Adenosina/análogos & derivados , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , RNA/metabolismo , Microambiente Tumoral , Adenosina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Carcinoma/tratamento farmacológico , Carcinoma/imunologia , Carcinoma/mortalidade , Estudos de Casos e Controles , Humanos , Linfócitos do Interstício Tumoral , Terapia de Alvo Molecular , Prognóstico , Proteínas de Ligação a RNA/metabolismoRESUMO
Ankylosing spondylitis (AS) is a chronic progressive autoimmune disease with insidious onset, high rates of disability among patients, unknown pathogenesis, and no effective treatment. Ferroptosis is a novel type of regulated cell death that is associated with various cancers and diseases. However, its relation to AS is not clear. In the present study, we identified two potential therapeutic targets for AS based on genes associated with ferroptosis and explored their association with immune cells and immune cell infiltration (ICI). We studied gene expression profiles of two cohorts of patients with AS (GSE25101 and GSE41038) derived from the gene expression omnibus database, and ferroptosis-associated genes (FRGs) were obtained from the FerrDb database. LASSO regression analysis was performed to build predictive models for AS based on FRGs, and the ferroptosis level in each sample was assessed via single-sample gene set enrichment analysis. Weighted gene co-expression network and protein-protein interaction network analyses were performed for screening; two key genes, DDIT3 and HSPB1, were identified in patients with AS. The relationship between key genes and ICI levels was assessed using the CIBERSORT algorithm, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Finally, DDIT3 and HSPB1 were identified as diagnostic markers and potential therapeutic targets for AS. DDIT3 was highly positively correlated with the infiltration levels of various immune cells, while HSPB1 was negatively correlated with the infiltration levels of several different types of immune cells. In conclusion, DDIT3 and HSPB1 may induce ferroptosis in the cells of patients with AS via changes in the inflammatory response in the immune microenvironment, and these genes could serve as molecular targets for AS therapy.
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Intervertebral disc degeneration (IVDD) is a common pathological condition responsible for lower back pain, which can significantly increase economic and social burdens. Although considerable efforts have been made to identify potential mechanisms of disc degeneration, the treatment of IVDD is not satisfactory. Ferroptosis, a recently reported form of regulated cell death (RCD), is characterized by iron-dependent lipid peroxidation and has been demonstrated to be responsible for a variety of degenerative diseases. Accumulating evidence suggests that ferroptosis is implicated in IVDD by decreasing viability and increasing extracellular matrix degradation of nucleus pulposus cells, annulus fibrosus cells, or endplate chondrocytes. In this review, we summarize the literature regarding ferroptosis of intervertebral disc cells and discuss its molecular pathways and biomarkers for treating IVDD. Importantly, ferroptosis is verified as a promising therapeutic target for IVDD.
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Anel Fibroso , Ferroptose , Degeneração do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Degeneração do Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Disco Intervertebral/patologiaRESUMO
Objective: To investigate the effectiveness of transvertebral space and under the pedicle osteotomy for thoracolumbar kyphosis caused by old osteoporotic vertebral compression fracture (OVCF). Methods: The clinical data of 11 patients with thoracolumbar kyphosis caused by old OVCF treated by transvertebral space and under the pedicle osteotomy between January 2016 and December 2020 were retrospectively analyzed. There were 2 males and 9 females, with an average age of 61.3 years (range, 50-77 years) and with a median disease duration of 8 years (range, 6 months to 50 years). Fracture reasons: 9 cases had a clear history of trauma, and 2 cases had no obvious incentive. A total of 11 vertebrae was involved in fracture, including T 12 in 3, L 1 in 7, L 2 in 1. The operation time, intraoperative blood loss, postoperative drainage volume, and complications were recorded. Full-length X-ray films of spine and local X-ray films of the operation area were examined before operation, at 7 days after operation, and at last follow-up. The Cobb angle of thoracolumbar kyphosis was measured, and the correction rate was calculated. The visual analogue scale (VAS) score and Oswestry disability index (ODI) were recorded to assess patients' pain and functional improvement before operation, at 1 month after operation, and at last follow-up. Results: All operations were successfully completed. The average operation time was 188.6 minutes (range, 140-215 minutes); the average intraoperative blood loss was 268.2 mL (range, 100-500 mL); the average postoperative drainage volume was 615.5 mL (range, 160-1 500 mL). One patient developed bilateral thigh rebound pain after operation, which relieved after symptomatic treatment of nutritional nerve and acesodyne. All patients were followed up 14.7 months on average (range, 6-56 months). At last follow-up, osseous fusion was observed in all patients, and no fracture, loose, or displacement of internal fixator was observed on imaging. At 7 days after operation and at last follow-up, the Cobb angle of thoracolumbar kyphosis significantly improved when compared with preoperative one ( P<0.05), and there was no significant difference between at 7 days after operation and at last follow-up ( P>0.05); the correction rates of Cobb angle at 7 days after operation and at last follow-up were 68.0%±9.8% and 60.3%±11.9%, respectively. At 1 month after operation and at last follow-up, the VAS score and ODI significantly improved when compared with preoperative ones, and further improved at last follow-up when compared with those at 1 month after operation, all showing significant differences ( P<0.05). Conclusion: Transvertebral space and under the pedicle osteotomy is an effective way to treat thoracolumbar kyphosis caused by old OVCF with less trauma, shorter operation time, and less intraoperative blood loss. Patients can obtain good orthopedic results and quality of life.
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Fraturas por Compressão , Cifose , Fraturas da Coluna Vertebral , Feminino , Fraturas por Compressão/etiologia , Fraturas por Compressão/cirurgia , Humanos , Cifose/complicações , Cifose/cirurgia , Vértebras Lombares/lesões , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Osteotomia/métodos , Qualidade de Vida , Estudos Retrospectivos , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/cirurgia , Vértebras Torácicas/lesões , Vértebras Torácicas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Cardiogenic shock (CS) is the leading cause of the death in patients with ST elevation myocardial infarction (STEMI). Thyroid dysfunction is related to prognosis of patients with myocardial infarction. Hence, the aim of this study is to explore the relationship between thyroid hormones (free triiodothyronine [FT3] and free thyroxine [FT4]) and CS. METHODS: A total of 1270 patients with STEMI treated with percutaneous coronary intervention (PCI) were consecutively enrolled in our study. Patients were classified into two groups according to with or without CS during hospitalization. Stepwise multivariate logistic analysis was conducted to investigate the association of thyroid hormones and CS. Restricted cubic spline method was employed to further explore the relationship between CS and thyroid hormones. RESULTS: Patients who developed CS (n=103) had lower FT3 and higher FT4 upon admission. The stepwise logistic analysis showed both FT3 (P=0.038) and FT4 (P=0.024) were independently related to CS. Restricted cubic splines indicated that lower FT3 (<2.25 pg/ml) or higher FT4 (>1.25 ng/dl) were correlated with higher prevalence of CS. Over 2.5 years' follow-up, patients (n=294) with low FT3 (<2.85 pg/ml) and high FT4 (>=0.88 ng/dl) had the highest all-cause mortality (18.2%), whereas patients (n=293) with high FT3 and low FT4 had the lowest all-cause mortality (3.8%) (P for trend <0.0001). CONCLUSIONS: Both FT3 and FT4 were independently associated with in-hospital CS development in patients with STEMI treated with PCI. Patients with lower range of FT3 and upper range of FT4 had the worst outcomes in long-term follow-up.
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Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Choque Cardiogênico/epidemiologia , Choque Cardiogênico/etiologia , Choque Cardiogênico/terapia , Tri-IodotironinaRESUMO
The subsequent dislocation of a contralateral patellofemoral joint sometimes occurs after a first-time lateral patellar dislocation (LPD). However, the anatomic risk factors for subsequent contralateral LPD remain elusive. This study included 17 patients with contralateral LPD and 34 unilateral patellar dislocators. The anatomic parameters of the contralateral patellofemoral joints were measured using CT images and radiographs that were obtained at the time of the first dislocation. The Wilcoxon rank-sum test was performed, and a binary regression model was established to identify the risk factors. The receiver operating characteristic curves and the area under the curve (AUC) were analyzed. The tibial tubercle-Roman arch (TT-RA) distance was significantly different between patients with and without contralateral LPD (24.1 vs. 19.5 mm, p < 0.001). The hip−knee−ankle (HKA) angle, patellar tilt, congruence angle, and patellar displacement were greater in the study group than in the control group (p < 0.05). The TT-RA distance revealed an OR of 1.35 (95% CI (1.26−1.44]), p < 0.001) and an AUC of 0.727 for predicting contralateral LPD. The HKA angle revealed an OR of 1.74 (95% CI (1.51−2.00), p < 0.001) and an AUC of 0.797. The Patellar tilt, congruence angle, and patellar displacement had AUC values of 0.703, 0.725, and 0.817 for predicting contralateral LPD, respectively. In conclusion, the contralateral patellofemoral anatomic parameters were significantly different between patients with and without subsequent contralateral LPD. Increased TT-RA distance and excessive valgus deformity were risk factors and could serve as predictors for contralateral LPD. At first-time dislocation, the abnormal position of the patella relative to the trochlea may also be an important cause of subsequent LPD.
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Globally, osteosarcoma (OS) is the most prevalent form of primary bone cancer in children and adolescents. Traditional neoadjuvant chemotherapy regimens have reached a bottleneck; thus, OS survivors have unsatisfactory outcomes. Theaflavin-3,3'-digallate (TF3) exhibits potent anticancer properties against many human cancers. Nevertheless, the biological effects and the underlying molecular mechanism of TF3 in human OS remain unclear. The objective of this study was to investigate the effects of TF3 on human OS cell lines and mouse xenograft models. The results showed that TF3 reduced cell viability, suppressed cell proliferation, and caused G0/G1 cell cycle arrest in both MG63 and HOS cell lines in a concentration-dependent manner. TF3 also altered the homeostatic mechanisms for iron storage in the examined cell lines, resulting in an excess of labile iron. Unsurprisingly, TF3 caused oxidative stress through reduced glutathione (GSH) exhaustion, reactive oxygen species (ROS) accumulation, and the Fenton reaction, which triggered ferroptosis and apoptosis in the cells. TF3 also induced MAPK signalling pathways, including the ERK, JNK, and p38 MAPK pathways. Furthermore, oxidative stress was shown to be the primary reason for TF3-induced proliferation inhibition, programmed cell death, and MAPK pathway activation in vitro. Moreover, TF3 exhibited markedly strong antitumour efficacy in vivo in mouse models. In summary, this study demonstrates that TF3 concomitantly plays dual roles in apoptotic and ferroptotic cell death by triggering the ROS and MAPK signalling pathways in both in vitro and in vivo models.
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Neoplasias Ósseas , Ferroptose , Osteossarcoma , Camundongos , Animais , Criança , Humanos , Adolescente , Espécies Reativas de Oxigênio/metabolismo , Xenoenxertos , Linhagem Celular Tumoral , Apoptose , Osteossarcoma/tratamento farmacológico , Proliferação de Células , Antioxidantes/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Ferro/farmacologiaRESUMO
Elevated intraspinal pressure (ISP) following traumatic spinal cord injury (tSCI) can be an important factor for secondary SCI that may result in greater tissue damage and functional deficits. Our present study aimed to investigate the dynamic changes in ISP after different degrees of acute compression SCI in rabbits with closed canals and explore its influence on spinal cord pathophysiology. Closed balloon compression injuries were induced with different inflated volumes (40 µl, 50 µl or no inflation) at the T7/8 level in rabbits. ISP was monitored by a SOPHYSA probe at the epicenter within 7 days post-SCI. Edema progression, spinal cord perfusion and damage severity were evaluated by serial multisequence MRI scans, somatosensory evoked potentials (SEPs) and behavioral scores. Histological and blood spinal cord barrier (BSCB) permeability results were subsequently analyzed. The results showed that the ISP waveforms comprised three peaks, significantly increased after tSCI, peaked at 72 h (21.86 ± 3.13 mmHg) in the moderate group or 48 h (31.71 ± 6.02 mmHg) in the severe group and exhibited "slow elevated and fast decreased" or "fast elevated and slow decreased" dynamic changes in both injured groups. Elevated ISP after injury was correlated with spinal cord perfusion and edema progression, leading to secondary lesion enlargement. The secondary damage aggravation can be visualized by diffusion tensor tractography (DTT). Moreover, the BSCB permeability was significantly increased at the epicenter and rostrocaudal segments at 72 h after SCI; by 14 days, notable permeability was still observed at the caudal segment in the severely injured rabbits. Our results suggest that the ISP of rabbits with closed canals increased after acute compression SCI and exhibited different dynamic change patterns in moderately and severely injured rabbits. Elevated ISP exacerbated spinal cord perfusion, drove edema progression and led to secondary lesion enlargement that was strongly associated with BSCB disruption. For severe tSCI, early intervention targeting elevated ISP may be an indispensable choice to rescue spinal cord function.
Assuntos
Traumatismos da Medula Espinal , Animais , Edema/diagnóstico por imagem , Edema/etiologia , Potenciais Somatossensoriais Evocados , Imageamento por Ressonância Magnética , Coelhos , Medula Espinal/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/patologiaRESUMO
Enhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.
Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Elementos Facilitadores Genéticos , RNA não Traduzido/genética , Atlas como Assunto , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinogênese/imunologia , Carcinogênese/patologia , Linhagem Celular Tumoral , Nanismo Hipofisário/genética , Nanismo Hipofisário/imunologia , Proteína 7 de Ligação a Ácidos Graxos/genética , Proteína 7 de Ligação a Ácidos Graxos/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Células MCF-7 , Modelos Moleculares , Invasividade Neoplásica , Conformação de Ácido Nucleico , Ligação Proteica , Conformação Proteica , RNA não Traduzido/imunologia , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Análise de Sobrevida , Transcrição Gênica , Microambiente Tumoral , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologiaRESUMO
BACKGROUND: Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME). However, their contribution to the immunosuppressive status of the TME remains unclear. METHODS: We integrated single-cell sequencing and transcriptome data from different tumor types to uncover the molecular features of TAMs. In vitro experiments and prospective clinical tests confirmed the results of these analysis. RESULTS: We first detected intra- and inter-tumoral heterogeneities between TAM subpopulations and their functions, with CD86+ TAMs playing a crucial role in tumor progression. Next, we focused on the ligand-receptor interactions between TAMs and tumor cells in different TME phenotypes and discovered that aberrant expressions of six hub genes, including FLI1, are involved in this process. A TAM-tumor cell co-culture experiment proved that FLI1 was involved in tumor cell invasion, and FLI1 also showed a unique pattern in patients. Finally, TAMs were discovered to communicate with immune and stromal cells. CONCLUSION: We determined the role of TAMs in the TME by focusing on their communication pattern with other TME components. Additionally, the screening of hub genes revealed potential therapeutic targets.