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JOURNAL/nrgr/04.03/01300535-202502000-00032/figure1/v/2024-05-28T214302Z/r/image-tiff Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury. Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction. However, the mechanisms involved remain unclear. In this study, we found that after spinal cord injury, resting microglia (M0) were polarized into pro-inflammatory phenotypes (MG1 and MG3), while resting astrocytes were polarized into reactive and scar-forming phenotypes. The expression of growth arrest-specific 6 (Gas6) and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury. In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia, and even inhibited the cross-regulation between them. We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway. This, in turn, inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways. In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord, thereby promoting tissue repair and motor function recovery. Overall, Gas6 may play a role in the treatment of spinal cord injury. It can inhibit the inflammatory pathway of microglia and polarization of astrocytes, attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment, and thereby alleviate local inflammation and reduce scar formation in the spinal cord.
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Neuroligin-3 (Nlgn3) is an autism-associated cell-adhesion molecule that interacts with neurexins and is robustly expressed in both neurons and astrocytes. Neuronal Nlgn3 is an essential regulator of synaptic transmission but the function of astrocytic Nlgn3 is largely unknown. Given the high penetrance of Nlgn3 mutations in autism and the emerging role of astrocytes in neuropsychiatric disorders, we here asked whether astrocytic Nlgn3 might shape neural circuit properties in the cerebellum similar to neuronal Nlgn3. Imaging of tagged Nlgn3 protein produced by CRISPR/Cas9-mediated genome editing showed that Nlgn3 is enriched in the cell body but not the fine processes of cerebellar astrocytes (Bergmann glia). Astrocyte-specific knockout of Nlgn3 did not detectably alter the number of synapses, synaptic transmission, or astrocyte morphology in mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift in gene expression among multiple cerebellar cell types after the deletion of astrocytic Nlgn3. Hence, in contrast to neuronal Nlgn3, astrocytic Nlgn3 in the cerebellum is not involved in shaping synapses but may modulate gene expression in specific brain areas.
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Because of its insensitivity to existing radiotherapy, namely chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/ß-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated wnt/ß-catenin pathway of TNBC tissues, lnc-WAL (wnt/ß-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/ß-catenin pathway activation compared with the inactivation group. RIP-seq was used to compare the ß-catenin and IgG groups, where lnc-WAL could interact with ß-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted EMT, the proliferation, migration and invasion of breast cancer stem cells (BCSCs), and TNBC cells. Mechanistically, lnc-WAL inhibited ß-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, ß-catenin accumulated in the nucleus and activated the target genes. Importantly, wnt/ß-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/ß-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/ß-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for TNBC patients.
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Breast phyllodes tumor (PT) is a rare fibroepithelial neoplasm with potential malignant behavior. Long non-coding RNAs (lncRNAs) play multifaceted roles in various cancers, but their involvement in breast PT remains largely unexplored. In this study, microarray was leveraged for the first time to investigate the role of lncRNA in PT. We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT, and its overexpression endowed PT with high tumor grade and adverse prognosis. Furthermore, we elucidated that ZFPM2-AS1 promotes the proliferation, migration, and invasion of malignant PT in vitro. Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft (PDX) model could effectively inhibit tumor progression in vivo. Mechanistically, our findings showed that ZFPM2-AS1 is competitively bound to CDC42, inhibiting ACK1 and STAT1 activation, thereby launching the transcription of TNFRSF19. In conclusion, our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT, and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.
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A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.
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Neoplasias da Mama , Diferenciação Celular , Dieta Hiperlipídica , Progressão da Doença , Microbioma Gastrointestinal , Leucina , Células Supressoras Mieloides , Animais , Dieta Hiperlipídica/efeitos adversos , Leucina/metabolismo , Feminino , Humanos , Camundongos , Células Supressoras Mieloides/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/microbiologia , Neoplasias da Mama/metabolismo , Obesidade/microbiologia , Obesidade/metabolismo , Obesidade/patologia , Linhagem Celular TumoralRESUMO
Osteosarcoma (OS) is a prevalent bone solid malignancy that primarily affects adolescents, particularly boys aged 14-19. This aggressive form of cancer often leads to deadly lung cancer due to its high migration ability. Experimental evidence suggests that programmed cell death (PCD) plays a crucial role in the development of osteosarcoma. Various forms of PCD, including apoptosis, ferroptosis, autophagy, necroptosis, and pyroptosis, contribute significantly to the progression of osteosarcoma. Additionally, different signaling pathways such as STAT3/c-Myc signal pathway, JNK signl pathway, PI3k/AKT/mTOR signal pathway, WNT/ß-catenin signal pathway, and RhoA signal pathway can influence the development of osteosarcoma by regulating PCD in osteosarcoma cell. Therefore, targeting PCD and the associated signaling pathways could offer a promising therapeutic approach for treating osteosarcoma.
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Apoptose , Neoplasias Ósseas , Osteossarcoma , Transdução de Sinais , Osteossarcoma/patologia , Osteossarcoma/terapia , Osteossarcoma/metabolismo , Humanos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Neoplasias Ósseas/metabolismo , Autofagia , Ferroptose , Necroptose , AnimaisRESUMO
Disulfidptosis is a newly discovered form of regulatory cell death. However, the identification of disulfidptosis-related molecular subtypes and potential biomarkers in gliomas and their prognostic predictive potential need to be further elucidated. RNA sequencing profiles and the relevant clinical data were obtained from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Disulfidptosis-related clusters were identified by unsupervised clustering analysis. Immune cell infiltration analysis and drug sensitivity analysis were used to explore the differences between clusters. Gene set enrichment analysis (GSEA) of differential genes between clusters was performed to explore the potential biological functions and signaling. A disulfidptosis-related scoring system (DRSS) was constructed based on a combined COX and LASSO analysis. Mendelian randomization (MR) analyses were used to further explore the causal relationship between levels of genes in DRSS and an increased risk of glioma. A prognosis nomogram was constructed based on the DRSS and 3 clinical features (age, WHO stage, and IDH status). The accuracy and stability of the prognosis nomogram were also validated in different cohorts. We identified two clusters that exhibited different prognoses, drug sensitivity profiles, and tumor microenvironment infiltration profiles. The overall survival (OS) of Cluster2 was significantly better than Cluster1. Cluster1 had an overall greater infiltration of immune cells compared to Cluster2. However, the Monocytes, activated B cells had higher infiltration abundance in Cluster2. GSEA results showed significant enrichment of immune-related biological processes in Cluster1, while Cluster2 was more enriched for functions related to neurotransmission and regulation. PER3, RAB34, NKX3-2, GPX7, FRA10AC1, and TGIF1 were finally included to construct DRSS. DRSS was independently related to prognosis. There was a significant difference in overall survival between the low-risk score group and the high-risk score group. Among six genes in DRSS, GPX7 levels were demonstrated to have a causal relationship with an increased risk of glioma. GPX7 may become a more promising biomarker for gliomas. The prognosis nomogram constructed based on the DRSS and three clinical features has considerable potential for predicting the prognosis of patients with glioma. Free online software for implementing this nomogram was established: https://yekun-zhuang.shinyapps.io/DynNomapp/ . Our study established a novel glioma classification based on the disulfidptosis-related molecular subtypes. We constructed the DRSS and the prognosis nomogram to accurately stratify the prognosis of glioma patients. GPX7 was identified as a more promising biomarker for glioma. We provide important insights into the treatment and prognosis of gliomas.
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Glioma , Humanos , Biomarcadores , Morte Celular , Glioma/diagnóstico , Glioma/genética , Microambiente TumoralRESUMO
Stretchable electronics that prevalently adopt chemically inert metals as sensing layers and interconnect wires have enabled high-fidelity signal acquisition for on-skin applications. However, the weak interfacial interaction between inert metals and elastomers limit the tolerance of the device to external friction interferences. Here, we report an interfacial diffusion-induced cohesion strategy that utilizes hydrophilic polyurethane to wet gold (Au) grains and render them wrapped by strong hydrogen bonding, resulting in a high interfacial binding strength of 1017.6 N/m. By further constructing a nanoscale rough configuration of the polyurethane (RPU), the binding strength of Au-RPU device increases to 1243.4 N/m, which is 100 and 4 times higher than that of conventional polydimethylsiloxane and styrene-ethylene-butylene-styrene-based devices, respectively. The stretchable Au-RPU device can remain good electrical conductivity after 1022 frictions at 130 kPa pressure, and reliably record high-fidelity electrophysiological signals. Furthermore, an anti-friction pressure sensor array is constructed based on Au-RPU interconnect wires, demonstrating a superior mechanical durability for concentrated large pressure acquisition. This chemical modification-free approach of interfacial strengthening for chemically inert metal-based stretchable electronics is promising for three-dimensional integration and on-chip interconnection.
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Objective: Frequent teacher turnover may damage the development of teachers and the regular operation of kindergartens. This original research presented kindergarten teachers' first, second, and third turnover rates and occurrence times. This research analyzed the relationship between socio-demographic variables and the varying frequency of kindergarten teacher turnover. These data were used to investigate the characteristics of first, second, and third kindergarten turnover. This research evaluated kindergarten teachers' occupational ambition, emotional attachment, and self-efficacy. Likewise, this research also analyzed the social context, organizational support, management mechanism, reward, and occupational stress of kindergarten. These data were used to determine the key factors affecting kindergarten teachers' turnover. Methods: This research recruited 1,118 kindergarten teachers (mean age = 31.67, sd = 5.02; 3.85% male, 96.14% female) from China. Based on the existing scales, this research developed the Questionnaire of Kindergarten Teachers' Turnover and Influencing Factors for the survey. Kindergarten teachers reported basic information and the impact factors of their first, second, and third turnover through online questionnaires. The Chi-square test was used to analyze the correlation between socio-demographic variables and different frequencies of kindergarten teacher turnover. The binary logistic regression explored the eight factors affecting kindergarten teachers' first, second, and third turnover. Results: The results showed that 43.65% of kindergarten teachers had resigned. In detail, 25.60% of kindergarten teachers resigned once, 10.64% of kindergarten teachers resigned twice, and 8.41% of kindergarten teachers resigned thrice. Gender and marital status were significantly correlated with the three frequencies of kindergarten teacher turnover. Occupational stress, reward, management mechanisms, and ambition consistently affected kindergarten teachers' first, second, and third turnover. Conclusion: The relevant management departments should pay attention to the high turnover rate of kindergarten teachers and put forward more strategies to improve their stability. Women and married can be favored in the recruitment of kindergarten teachers. It is crucial to reduce pressure and improve rewards for kindergarten teachers. Also, kindergartens should provide the space to display teachers' talents and improve management mechanisms. These results provide empirical support for proposing effective policies to promote the stability of kindergarten teachers' construction.
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Removing the overexpressed TNF-α by hemoperfusion positively affects clinical treatments for diseases such as autoimmune disease and sepsis. However, clearance ratios of adsorbents targeting TNF-α were limited by the extremely low concentration of TNF-α (mostly <1000 ng/L in sepsis) and hydrophobic interactions. In this work, biparatopic nanobodies (NbC21) with a high affinity of 19.9 pM, which bind to two distinct sites of TNF-α, were constructed as high-affinity ligands for the immunosorbent. The theoretical maximum adsorption capacity estimated from the Langmuir isotherm was up to 18.22 mg/g gel. The prepared immunosorbent (NbC21-sorbent) had an outstanding TNF-α clearance ratio of approximately 96% during the dynamic adsorption test, with a sorbent-to-serum ratio of 1:1000. Additionally, it demonstrated favorable hemocompatibility and a prolonged storage capability. The results indicated that the biparatopic nanobody immunosorbent exhibited significant potential for clinical applications as it met the stringent criteria for both efficacy and safety.
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Sepse , Fator de Necrose Tumoral alfa , Humanos , Imunoadsorventes , Sepse/tratamento farmacológicoRESUMO
BACKGROUND: The potential link between environmental pollutants, including metals, and schizophrenia development remains debated. This study aimed to explore the association between plasma levels of three non-essential metals-barium (Ba), tungsten (W), and uranium (U)-and schizophrenia risk among Chinese individuals. METHOD: We recruited a total of 221 patients and 219 healthy controls. Plasma levels of three non-essential metals were measured using inductively coupled plasma mass spectrometry. We employed unconditional logistic regression and Bayesian kernel machine regression (BKMR) to explore the relationship between exposure to multiple metals and the risk of schizophrenia. RESULTS: Logistic regression analysis revealed that the highest quartile (Q4) of W had an odds ratio (OR) of 1.87 (95% CI: 1.08-3.21) compared to the lowest quartile (Q1), with a significant P-trend of 0.017. For U, the ORs (95% CI) for Q2, Q3, and Q4 were 2.06 (1.19-3.56), 1.99 (1.15-3.44), and 1.74 (1.00-3.00), respectively. BKMR analyses revealed a progressive increase in the risk of schizophrenia with increasing cumulative levels of the three metals at concentrations below 35%, with U playing a major role in this association. U showed a non-linear positive correlation with schizophrenia, particularly at the 75th percentile level. Moreover, potential interactions were observed between W and Ba, as well as between W and U. CONCLUSION: Higher plasma W and U concentrations were positively associated with the risk of schizophrenia, which was potentially related to the severity of symptoms in schizophrenic patients.
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Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.
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Neoplasias Nasofaríngeas , Camundongos , Animais , Humanos , Neoplasias Nasofaríngeas/terapia , Herpesvirus Humano 4 , Receptores de Antígenos de Linfócitos T , Linfócitos T CD4-Positivos , Imunoterapia , Imunoterapia Adotiva/métodos , Microambiente TumoralRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a pathological subtype with a high mortality, and the development of inhibitors in the ubiquitin-proteasome system (UPS) component could be a novel therapeutic tool. METHODS: Triple-negative breast cancer data were obtained from The Cancer Genome Atlas (TCGA), and subtype analysis was performed by consistent clustering analysis to identify molecular subtypes of TNBC according to UPS characteristics. Differential analysis, COX and least absolute shrinkage and selection operator (LASSO) COX regression analyses were performed to select genes associated with overall survival in TNBC. The final prognostic model (UPS score) was determined using the LASSO COX model. The model performance was assessed using receiver operating characteristic (ROC) curves and survival curves. In addition, the results of the UPS score on analyzing the abundance of immune cell infiltration and immunotherapy were explored. Finally, we developed a nomogram for TNBC survival prediction. RESULTS: Two UPS subtypes (UPSMS1 and UPSMS2) showing significant survival differences were classified. COX regression analysis on differentially expressed genes in UPSMS1 and UPSMS2 filtered five genes that affected overall survival. Based on the regression coefficients and expression data of the five genes, we built a prognostic assessment system (UPS score). The UPS score showed consistent prognostic and therapeutic guidance values. Finally, the ROC curve of the nomogram and UPS score showed the highest predictive efficacy compared with traditional clinical prognostic indicators. CONCLUSION: The UPS score represented a promising prognostic tool to predict overall survival and immune status and guide personalized treatment selection in TNBC patients, and this study may provide a more practical alternative for clinical monitoring and management of TNBC.
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Complexo de Endopeptidases do Proteassoma , Neoplasias de Mama Triplo Negativas , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Citoplasma , Imunoterapia , UbiquitinasRESUMO
BACKGROUND: As a rapid-progressing tumor, breast malignant phyllodes tumors (PTs) are challenged by the lack of effective therapeutic strategies and suitable prognostic markers. This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression, and to identify a novel prognosis marker and treatment target of breast malignant PTs. METHODS: The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing (scRNA-seq), immunostaining, real-time PCR and other methodologies. Functional experiments including proliferation assay, colony formation assay, transwell assay, and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs. The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft (PDX) model. Transcriptome sequencing, proteomic analysis, co-immunoprecipitation, and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism. RESULTS: In this study, the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in the α-SMA+ fibroblast subset. Furthermore, a progressive elevation in the level of CD146 was observed with the malignant progression of PTs. More importantly, CD146 was found to serve as an independent predictor for recurrence in PT patients. Furthermore, CD146 was found to augment the viability and invasion of PTs. Mechanistically, CD146 acted as a protective "shield" to prevent the degradation of Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2), thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and enhancing malignant behaviors of PT cells. In the malignant PT organoid and PDX model, a significant suppression of malignant PT growth was observed after the application of AA98. CONCLUSIONS: These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs. The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.
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Neoplasias da Mama , Tumor Filoide , Animais , Feminino , Humanos , Neoplasias da Mama/patologia , Antígeno CD146/genética , Modelos Animais de Doenças , Proteínas de Membrana , Fosfatidilinositol 3-Quinases , Tumor Filoide/genética , Tumor Filoide/metabolismo , Tumor Filoide/patologia , Proteômica , Proteínas Proto-Oncogênicas c-aktRESUMO
Removing excessively produced cytokines is of paramount significance in blood purification therapy for hypercytokinemia-associated diseases. In this study, we devised a conduit that is modified with nanobodies (Nb) and incorporates static mixers (Nb-SMC) to eliminate surplus cytokines from the bloodstream. The low-pressure-drop (LPD) static mixer, with each unit featuring two 90°-crossed blades, was strategically arranged in a tessellated pattern on the inner wall of the conduit to induce turbulent mixing effects during the flow of blood. This arrangement enhances mass transfer and molecular diffusion, thereby assisting in the identification and elimination of cytokines. By utilizing computational fluid dynamics (CFD) studies, the Nb-SMC was rationally designed and prepared, ensuring an optimal interval between two mixer units (H/G = 2.5). The resulting Nb-SMC exhibited a remarkable selective clearance of IL-17A, reaching up to 85 %. Additionally, the process of Nb immobilization could be adjusted to achieve the simultaneous removal of multiple cytokines from the bloodstream. Notably, our Nb-SMC displayed good blood compatibility without potential adverse effects on the composition of human blood. As the sole documented static mixer-integrated conduit capable of selectively eliminating cytokines at their physiological concentrations, it holds promise in the clinical potential for hypercytokinemia in high-risk patients. STATEMENT OF SIGNIFICANCE: High-efficient cytokines removal in critical care still remains a challenge. The conduit technique we proposed here is a brand-new strategy for cytokines removal in blood purification therapy. On the one hand, nanobody endows the conduit with specific recognition of cytokine, on the other hand, the build-in static mixer enhances the diffusion of antigenic cytokine to the ligand. The combination of these two has jointly achieved the efficient and specific removal of cytokine. This innovative material is the only reported artificial biomaterial capable of selectively eliminating multiple cytokines under conditions close to clinical practice. It has the potential to improve outcomes for patients with hypercytokinemia and reduce the risk of adverse events associated with current treatment modalities.
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Citocinas , Hemoperfusão , Humanos , Hemoperfusão/métodos , Síndrome da Liberação de Citocina , Próteses e ImplantesRESUMO
Individuals with spinal cord injury (SCI) suffer from permanent disabilities such as severe motor, sensory and autonomic dysfunction. Neural stem cell transplantation has proven to be a potential strategy to promote regeneration of the spinal cord, since NSCs can produce neurotrophic growth factors and differentiate into mature neurons to reconstruct the injured site. However, it is necessary to optimize the differentiation of NSCs before transplantation to achieve a better regenerative outcome. Inhibition of Notch signaling leads to a transition from NSCs to neurons, while the underlying mechanism remains inadequately understood. Our results demonstrate that overexpression of fucosyltransferase 9 (Fut9), which is upregulated by Wnt4, promotes neuronal differentiation by suppressing the activation of Notch signaling through disruption of furin-like enzyme activity during S1 cleavage. In an in vivo study, Fut9-modified NSCs efficiently differentiates into neurons to promote functional and histological recovery after SCI. Our research provides insight into the mechanisms of Notch signaling and a potential treatment strategy for SCI.
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Fucosiltransferases , Traumatismos da Medula Espinal , Animais , Ratos , Diferenciação Celular/fisiologia , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/terapia , Receptores Notch/metabolismoRESUMO
New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cell receptor (TCR) T cell therapy is effective in tumors with NY-ESO-1 expression, but a safe and effective TCR-T cell therapeutic protocol remains to be improved. Here, we report a phase 1 investigational new drug clinical trial with TCR affinity-enhanced specific T cell therapy (TAEST16001) for targeting NY-ESO-1. Enrolled patients receive TAEST16001 cell infusion after dose-reduced lymphodepletion with cyclophosphamide (15 mg/kg/day × 3 days) combined with fludarabine (20 mg/m2/day × 3 days), and the TCR-T cells are maintained with low doses of interleukin-2 injection post-adoptive transfer. Analysis of 12 patients treated with the regimen demonstrates no treatment-related serious adverse events. The overall response rate is 41.7%. The median progression-free survival is 7.2 months, and the median duration of response is 13.1 months. The protocol of TAEST16001 cells delivers a safe and highly effective treatment for patients with advanced soft tissue sarcoma (ClinicalTrials.gov: NCT04318964).
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Imunoterapia Adotiva , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Antígenos HLA-A/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/terapia , Linfócitos TRESUMO
BACKGROUND: Metabolites secreted by the gut microbiota may play an essential role in microbiota-gut-central nervous system crosstalk. In this study, we explored the changes occurring in the gut microbiota and their metabolites in patients with spinal cord injury (SCI) and analyzed the correlations among them. METHODS: The structure and composition of the gut microbiota derived from fecal samples collected from patients with SCI (n = 11) and matched control individuals (n = 10) were evaluated using 16S rRNA gene sequencing. Additionally, an untargeted metabolomics approach was used to compare the serum metabolite profiles of both groups. Meanwhile, the association among serum metabolites, the gut microbiota, and clinical parameters (including injury duration and neurological grade) was also analyzed. Finally, metabolites with the potential for use in the treatment of SCI were identified based on the differential metabolite abundance analysis. RESULTS: The composition of the gut microbiota was different between patients with SCI and healthy controls. At the genus level, compared with the control group, the abundance of UBA1819, Anaerostignum, Eggerthella, and Enterococcus was significantly increased in the SCI group, whereas that of Faecalibacterium, Blautia, Escherichia-Shigella, Agathobacter, Collinsella, Dorea, Ruminococcus, Fusicatenibacter, and Eubacterium was decreased. Forty-one named metabolites displayed significant differential abundance between SCI patients and healthy controls, including 18 that were upregulated and 23 that were downregulated. Correlation analysis further indicated that the variation in gut microbiota abundance was associated with changes in serum metabolite levels, suggesting that gut dysbiosis is an important cause of metabolic disorders in SCI. Finally, gut dysbiosis and serum metabolite dysregulation was found to be associated with injury duration and severity of motor dysfunction after SCI. CONCLUSIONS: We present a comprehensive landscape of the gut microbiota and metabolite profiles in patients with SCI and provide evidence that their interaction plays a role in the pathogenesis of SCI. Furthermore, our findings suggested that uridine, hypoxanthine, PC(18:2/0:0), and kojic acid may be important therapeutic targets for the treatment of this condition.
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Microbioma Gastrointestinal , Traumatismos da Medula Espinal , Humanos , Microbioma Gastrointestinal/genética , Disbiose/microbiologia , RNA Ribossômico 16S/genética , Traumatismos da Medula Espinal/patologia , Fezes/microbiologiaRESUMO
Experimental studies have shown that exercise and human adipose-derived stem cells (ADSCs) play positive roles in spinal cord injury (SCI). However, whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear. Thus, there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI. In this study, a thoracic 11 (T11) SCI contusion model was established in adult C57BL/6 mice. Exercise was initiated from 7 days post-injury and continued to 28 days post-injury, and approximately 1 × 105 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI. Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale, von Frey filament test, Hargreaves method, and cold plate test. Histological studies (Eriochrome cyanine staining and immunohistochemistry) were performed at the end of the experiment (28 days post-injury). Exercise combined with administration of ADSCs partially improved early motor function (7, 14, and 21 days post-injury), mechanical allodynia, mechanical hypoalgesia, thermal hyperalgesia, and thermal hypoalgesia. Administration of ADSCs reduced white and gray matter loss at the lesion site. In addition, fewer microglia and astrocytes (as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, respectively) were present in the lumbar dorsal horn in the SCI + ADSCs and SCI + exercise + ADSCs groups compared with the sham group. Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCI-induced neuropathic pain.
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Neural stem cells (NSCs) transplantation has been considered as a potential strategy to reconnect the neural circuit after spinal cord injury (SCI) but the therapeutic effect was still unsatisfied because of the poor inflammatory micro-environment of SCI. Previous study reported that neuroprotection and inflammatory immunomodulation were considered to be most important mechanism of NSCs transplantation. In addition, Wnt4 has been considered to be neurogenesis and anti-inflammatory so that it would be an essential assistant agent for NSCs transplantation. Our single cells sequence indicates that macrophages are the most important contributor of inflammatory response after SCI and the interaction between macrophages and astrocytes may be the most crucial to inflammatory microenvironment of SCI. We further report the first piece of evidence to confirm the interaction between Wnt4-modified NSCs and macrophages using NSCs-macrophages co-cultured system. Wnt4-modified NSCs induce M2 polarization and inhibit M1 polarization of macrophages through suppression of TLR4/NF-κB signal pathway; furthermore, M2 cells promote neuronal differentiation of NSCs through MAPK/JNK signal pathway. In vivo, transplantation of Wnt4-modified NSCs improves inflammatory micro-environment through induce M2 polarization and inhibits M1 polarization of macrophages to promote axonal regeneration and tissue repair. The current study indicated that transplantation of Wnt4-modified NSCs mediates M2 polarization of macrophages to promote spinal cord injury repair. Our novel findings would provide more insight of SCI and help with identification of novel treatment strategy.