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It is necessary to predict the critical transition of lake ecosystems due to their abrupt, non-linear effects on social-economic systems. Given the promising application of paleolimnological archives to tracking the historical changes of lake ecosystems, it is speculated that they can also record the lake's critical transition. We studied Lake Dali-Nor in the arid region of Inner Mongolia because of the profound shrinking the lake experienced between the 1300 s and the 1600 s. We reconstructed the succession of bacterial communities from a 140-cm-long sediment core at 4-cm intervals and detected the critical transition. Our results showed that the historical trajectory of bacterial communities from the 1200 s to the 2010s was divided into two alternative states: state1 from 1200 to 1300 s and state2 from 1400 to 2010s. Furthermore, in the late 1300 s, the appearance of a tipping point and critical slowing down implied the existence of a critical transition. By using a multi-decadal time series from the sedimentary core, with general Lotka-Volterra model simulations, local stability analysis found that bacterial communities were the most unstable as they approached the critical transition, suggesting that the collapse of stability triggers the community shift from an equilibrium state to another state. Furthermore, the most unstable community harbored the strongest antagonistic and mutualistic interactions, which may imply the detrimental role of interaction strength on community stability. Collectively, our study showed that sediment DNA can be used to detect the critical transition of lake ecosystems.
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Bacterias , ADN Bacteriano , Sedimentos Geológicos , Lagos , Lagos/microbiología , Lagos/química , Sedimentos Geológicos/microbiología , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , China , ADN Bacteriano/genética , Ecosistema , ARN Ribosómico 16S/genética , MicrobiotaRESUMEN
Extensive infiltration by tumor-associated macrophages (TAM) in combination with myeloid-derived suppressor cells constitute the immunosuppressive microenvironment and promote the malignant phenotype of gliomas. The aggressive mesenchymal (MES)-subtype glioma stem cells (GSC) are prominent in the immunosuppressive microenvironment of gliomas. However, the underlying immune-suppressive mechanisms are still unknown. The current study showed that the antitumor immune microenvironment was activated in glioma in Nfat1-/- mice, suggesting induction of the immune-suppressive microenvironment by nuclear factor of activated T cells-1 (NFAT1). In TAMs, NFAT1 could upregulate the transcriptional activity of complement 3 (C3) and increase the secretion of C3a, which could then bind to C3aR and promote M2-like macrophage polarization by activating TIM-3. Simultaneously, C3a/C3aR activated the Ca2+-NFAT1 pathway, forming a positive feedback loop for the M2-like polarization of TAMs, which further promoted the MES transition of GSCs. Finally, disruption of this feedback loop using a C3aR inhibitor significantly inhibited glioma growth both in vitro and in vivo. The current study demonstrated that a NFAT1-C3a-C3aR positive feedback loop induces M2-like TAMs and further promotes the malignant phenotype of GSCs, which might be the potential therapeutic target for glioma.
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Glioma , Macrófagos , Animales , Ratones , Macrófagos Asociados a Tumores/metabolismo , Retroalimentación , Glioma/genética , Fenotipo , Células Madre Neoplásicas/metabolismo , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Glioma stem cells (GSCs) exhibit diverse molecular subtypes with the mesenchymal (MES) population representing the most malignant variant. The oncogenic potential of Salmonella pathogenicity island 1 (SPI1), an oncogenic transcription factor, has been established across various human malignancies. In this study, we explored the association between the SPI1 pathway and the MES GSC phenotype. Through comprehensive analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas glioma databases, along with patient-derived GSC cultures, we analyzed SPI1 expression. Using genetic knockdown and overexpression techniques, we assessed the functional impact of SPI1 on GSC MES marker expression, invasion, proliferation, self-renewal, and sensitivity to radiation in vitro, as well as its influence on tumor formation in vivo. Additionally, we investigated the downstream signaling cascades activated by SPI1. Our findings revealed a positive correlation between elevated SPI1 expression and the MES phenotype, which in turn, correlated with poor survival. SPI1 enhanced GSC MES differentiation, self-renewal, and radioresistance in vitro, promoting tumorigenicity in vivo. Mechanistically, SPI1 augmented the transcriptional activity of both TGF-ß1 and FKBP12 while activating the non-canonical PI3K/Akt pathway. Notably, inhibition of TGF-ß1/PI3K/Akt signaling partially attenuated SPI1-induced GSC MES differentiation and its associated malignant phenotype. Collectively, our results underscore SPI1's role in activating TGF-ß1/PI3K/Akt signaling through transcriptional upregulation of FKBP12, thereby supporting the aggressive MES phenotype of GSCs. Therefore, SPI1 emerges as a potential therapeutic target in glioma treatment.
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Glioma , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteína 1A de Unión a Tacrolimus/genética , Proteína 1A de Unión a Tacrolimus/metabolismo , Regulación hacia Arriba , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Islas Genómicas , Células Madre Neoplásicas/metabolismo , Glioma/patología , Fenotipo , Línea Celular Tumoral , Proliferación CelularRESUMEN
Objective: To investigate the levels of tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) and the expression of programmed cell death receptor ligand 1 (PD-L1) in the tumor microenvironment (TME) of pediatric and adolescent pituitary adenomas (PAPAs) and analyze the correlation between their levels and the clinical characteristics. Methods: A series of 43 PAPAs cases were enrolled over a period of 5 years. To compare the TME of PAPAs and adult PAs, 43 PAPAs cases were matched with 60 adult PAs cases (30 cases were between 20 and 40 years old, and 30 cases were older than 40 years) for main clinical characteristics. The expression of immune markers in PAPAs was detected by immunohistochemistry, and their correlation with the clinical outcomes was analyzed using statistical methods. Results: In the PAPAs group, CD8+ TILs level was significantly lower (3.4 (5.7) vs. 6.1 (8.5), p = 0.001), and PD-L1 expression (0.040 (0.022) vs. 0.024 (0.024), p < 0.0001) was significantly higher as compared with the older group. The level of CD8+ TILs was negatively correlated with the expression of PD-L1 (r = -0.312, p = 0.042). Moreover, CD8+ TILs and PD-L1 levels were associated with Hardy (CD8, p = 0.014; PD-L1, p = 0.018) and Knosp (CD8, p = 0.02; PD-L1, p = 0.017) classification. CD8+ TILs level was associated with high-risk adenomas (p = 0.015), and it was associated with the recurrence of PAPAs (HR = 0.047, 95% CI 0.003-0.632, p = 0.021). Conclusion: Compared with the TME in adult PAs, the TME in PAPAs was found to express a significantly altered level of CD8+ TILs and PD-L1. In PAPAs, CD8+ TILs and PD-L1 levels were associated with clinical characteristics.
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Adenoma , Neoplasias Hipofisarias , Adulto , Humanos , Adolescente , Niño , Adulto Joven , Neoplasias Hipofisarias/metabolismo , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos , Linfocitos Infiltrantes de Tumor , Adenoma/metabolismo , Microambiente TumoralRESUMEN
The nuclear factor of activated T cells (NFAT) was first identified as a transcriptional regulator of activated T cells. The NFAT family is involved in the development of tumors. Furthermore, recent evidence reveals that NFAT proteins regulate the development of inflammatory and immune responses. New discoveries have also been made about the mechanisms by which NFAT regulates cancer progression through cancer stem cells (CSC). Here, we discuss the role of the NFAT family in the immune system and various cancer types.
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Factores de Transcripción NFATC , Neoplasias , Humanos , Factores de Transcripción NFATC/metabolismo , Calcineurina/metabolismo , Transducción de Señal , Células Madre Neoplásicas/metabolismoRESUMEN
NiFe-layered double hydroxide (NiFe-LDH) is the benchmark catalyst for the oxygen evolution reaction (OER) in alkaline medium, however, it is still challenging to improve its activity and stability. Herein, NiFe-LDH macroporous array electrodes are demonstrated to significantly enhance the activity and stability for oxygen evolution reaction. The electrodes are fabricated by the chemical and electrochemical corrosion process of Ni foam induced by ferric nitrate, hydrochloric acid and oxygen. By optimizing the amount of iron salt and acid and selecting the appropriate reaction temperature and time, the NiFe-LDH electrodes only need the overpotential of 180â mV and 248â mV to reach the current density of 10â mA cm-2 and 500â mA cm-2 , respectively, and remain highly stable for 1000â h at 500â mA cm-2 . The unique macroporous array not only significantly increases the active area of NiFe-LDH catalyst, but also creates a stable nanostructure that avoids severe reconstruction.
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NiFe-based (oxy)hydroxides are the benchmark catalysts for the oxygen evolution reaction (OER) in alkaline medium, however, it is still challenging to control their structures and compositions. Herein, molybdates (NiFe(MoO4 )x ) are applied as unique precursors to synthesize ultrafine Mo modified NiFeOx Hy (oxy)hydroxide nanosheet arrays. The electrochemical activation process enables the molybdate ions (MoO4 2- ) in the precursors gradually dissolve, and at the same time, hydroxide ions (OH- ) in the electrolyte diffuse into the precursor and react with Ni2+ and Fe3+ ions in confined space to produce ultrafine NiFeOx Hy (oxy)hydroxides nanosheets (<10 nm), which are densely arranged into microporous arrays and maintain the rod-like morphology of the precursor. Such dense ultrafine nanosheet arrays produce rich edge planes on the surface of NiFeOx Hy (oxy)hydroxides to expose more active sites. More importantly, the capillary phenomenon of microporous structures and hydrophilic hydroxyl groups induce the superhydrophilicity and the rough surface produces the superaerophobic characteristic for bubbles. With these advantages, the optimized catalyst exhibits excellent performance for OER, with a small overpotential of 182 mV at 10 mA cm-2 and long-term stability (200 h) at 200 mA cm-2 . Theoretical calculations show that the modification of Mo enhances the electron delocalization and optimizes the adsorption of intermediates.
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OBJECTIVE: To investigate the expression of programmed death ligand-1 (PD-L1) and the levels of CD8+ tumor-infiltrating lymphocytes (TILs) in meningioma as well as determine the association between their levels and the clinical outcomes. METHODS: We performed a retrospective case-control study on 93 patients with meningioma. The patients showed tumor recurrence and were matched with the control patients without recurrence in their age, gender, admission time, tumor sites, tumor volume, peritumoral brain edema (PTBE), Simpson grade resection, WHO grade, postoperative radiotherapy, and the follow-up duration. We reviewed the clinical data of patients and performed immunohistochemistry analysis to investigate the PD-L1 expression and the levels of CD8+ TILs. Multivariate logistic regression was performed to analyze the association between clinical features and immune markers. The conditional logistic regression models were used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and Kaplan-Meier analysis was performed to analyze tumor recurrence. RESULTS: Tumor volume was correlated with the PD-L1 expression (P = 0.003, HR = 5.288, 95%CI, 1.786-15.651). PTBE served as an independent predictor of CD8+ TIL levels (P = 0.001, HR = 0.176, 95%CI 0.065-0.477). The levels of CD8+ TILs were associated with tumor recurrence (P = 0.020, OR = 0.325, 95%CI, 0.125-0.840). CONCLUSION: Tumor volume was associated with PD-L1 expression, and PTBE was an independent predictor of CD8+ TIL levels in meningioma. CD8+ TIL levels correlated with tumor recurrence in meningioma.
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Neoplasias Meníngeas , Meningioma , Humanos , Antígeno B7-H1/metabolismo , Meningioma/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Estudios Retrospectivos , Estudios de Casos y Controles , Linfocitos T CD8-positivos , Linfocitos Infiltrantes de Tumor , Neoplasias Meníngeas/metabolismo , PronósticoRESUMEN
Background: Glioma is the most prevalent malignant intracranial tumor. Many studies have shown that angiogenesis plays a crucial role in glioma tumorigenesis, metastasis, and prognosis. In this study, we conducted a comprehensive analysis of angiogenesis-related genes (ARGs) in glioma. Methods: RNA-sequencing data of glioma patients were obtained from TCGA and CGGA databases. Via consensus clustering analysis, ARGs in the sequencing data were distinctly classified into two subgroups. We performed univariate Cox regression analysis to determine prognostic differentially expressed ARGs and least absolute shrinkage and selection operator Cox regression to construct a 14-ARG risk signature. The CIBERSORT algorithm was used to explore immune cell infiltration, and the ESTIMATE algorithm was applied to calculate immune and stromal scores. Results: We found that the 14-ARG signature reflected the infiltration characteristics of different immune cells in the tumor immune microenvironment. Additionally, total tumor mutational burden increased significantly in the high-risk group. We combined the 14-ARG signature with patient clinicopathological data to construct a nomogram for predicting 1-, 3-, and 5-year overall survival with good accuracy. The predictive value of the prognostic model was verified in the CGGA cohort. SPP1 was a potential biomarker of glioma risk and was involved in the proliferation, invasion, and angiogenesis of glioma cells. Conclusion: In conclusion, we established and validated a novel ARG risk signature that independently predicted the clinical outcomes of glioma patients and was associated with the tumor immune microenvironment.
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BACKGROUND: The coexistence of meningioma and other intracranial primary benign tumors is rare, especially in non-neurofibromatosis type 2, and there is limited guidance for the management of such patients. Here, we report a series of 5 patients with concomitant meningioma and other intracranial benign tumors, including subependymoma and pituitary adenoma. CASE SUMMARY: Five non-neurofibromatosis type 2 patients with simultaneous occurrence of meningioma and other intracranial benign tumors were retrospectively reviewed. The patients had no history of previous irradiation. The clinical features, pre- and postoperative imaging, surgical procedure and pathological findings were extracted from electronic medical records. There were 4 female patients (80%) and 1 male patient (20%). The mean age was 42.8 years (range: 29-52 years). The coexisting tumors included subependymoma in 1 case (20%) and pituitary adenoma in 4 cases (80%). The most common clinical symptom was headache (3/5, 60%). Four patients (80%) underwent craniotomy. One patient (20%) underwent transsphenoidal surgery followed by transcranial operation. All tumor diagnoses were confirmed by histopathological examination. The mean follow-up was 38.8 mo (range: 23-96 mo), and all 5 patients were in a stable condition at the last follow-up. CONCLUSION: The simultaneous occurrence of meningioma and other intracranial benign tumors is a rare clinical event. Histological examination is necessary for the accurate diagnosis. Neurosurgeons should select the appropriate surgical strategy according to the clinical features of each patient, which may provide a more favorable prognosis for individual patients.
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Pituitary adenomas (PAs) have a low incidence in pediatric and adolescent patients, and their clinical characteristics remain unclear. As a severe complication of PA, apoplexy was investigated in young patients in the present study. Eighty patients younger than 20 years with PAs who underwent surgery were included and divided into an apoplexy group and non-apoplexy group. The clinical data of these two groups were statistically analyzed and compared. The study included 33 boys and 47 girls, with a mean age of 16.9 years. There were six (7.5%) adrenocorticotropic hormone-secreting, 13 (16.3%) growth hormone-secreting, 47 (58.7%) prolactin-secreting, and 14 (17.5%) non-functioning PAs. There were 34 (42.5%) patients in the apoplexy group and 46 (57.5%) patients in the non-apoplexy group. Pre-operatively, patients in the apoplexy group were more likely to have visual impairment (hazard ratio: 2.841, 95% confidence interval: 1.073-7.519; P = 0.033) and had poorer visual impairment scores than those in the non-apoplexy group (P = 0.027). Furthermore, a longer duration of symptoms before surgery was significantly correlated with a poorer visual outcome in the apoplexy group (R = - 1.204; P = 0.035). However, apoplexy was not associated with tumor type, tumor size, resection rate, or tumor recurrence. Tumor apoplexy is common in pediatric and adolescent patients with PAs and is associated with more severe preoperative visual deficits. Hence, the appropriate timing of surgical treatment may be important for rescuing visual function in young PA patients.
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Adenoma , Neoplasias Hipofisarias , Accidente Cerebrovascular , Adenoma/complicaciones , Adenoma/cirugía , Adolescente , Niño , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/cirugía , Estudios RetrospectivosRESUMEN
PURPOSE: Multifocal and multicentric glioblastomas (mGBMs) are associated with a poorer prognosis compared to unifocal glioblastoma (uGBM). The presence of CD8+ tumor-infiltrating lymphocytes (TILs) is predictive of clinical outcomes in human malignancies. Here, we examined the CD8+ lymphocytic infiltration in mGBMs. METHODS: The clinical data of 57 consecutive IDH wildtype primary mGBM patients with histopathological diagnoses were retrospectively reviewed. CD8+ TILs were quantitatively evaluated by immunohistochemical staining. The survival function of CD8+ TILs was assessed by Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: No significant difference in the concentration of CD8+ TILs was observed among foci from the same patient (P>0.150). The presence of CD8+ TILs was similar between multifocal and multicentric GBMs (P=0.885). The concentration of CD8+ TILs was significantly lower in mGBMs than in uGBMs (P=0.002). In mGBM patients, the CD8+ TIL level was associated with preoperative KPS (P=0.018). The median overall survival (OS) of the 57 mGBMs was 9 months. A low CD8+ TIL level (multivariate HR 4.404, 95% CI 1.954-9.926, P=0.0004) was an independent predictor of poor OS, while postoperative temozolomide chemotherapy (multivariate HR 6.076, 95% CI 2.330-15.842, P=0.0002) was independently associated with prolonged OS in mGBMs. CONCLUSIONS: Decreased CD8+ TIL levels potentially correlate with unfavorable clinical outcome in mGBMs, suggesting an influence of the local immuno-microenvironment on the progression of mGBMs.
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Mini-chromosome maintenance (MCM) proteins are critical components of DNA-replication-licensing factors. MCM8 is an MCM protein that exhibits oncogenic functions in several human malignancies. However, the role of MCM8 in glioblastomas (GBMs) has remained unclear. In the present study, we investigated the biological functions and mechanisms of MCM8 in glioma stem cells (GSCs). The clinical relevance of MCM8 mRNA expression was explored via TCGA and REMBRANDT datasets. The effects of MCM8 on the self-renewal and tumorigenicity of GSCs were examined both in vitro and in vivo. The regulation of MCM8 expression and its interacting proteins were also evaluated. We found that the expression of MCM8 was elevated in high-grade gliomas and classical molecular subtypes and was inversely correlated with patient prognosis. GSCs had a significantly higher expression of MCM8 compared with that in normal glioma cells. Silencing of MCM8 induced G0/G1 arrest and apoptosis, as well as inhibited the proliferation and self-renewal of GSCs. Forced expression of MCM8 enhanced clonogenicity of GSCs both in vitro and in vivo. MCM8 expression was regulated by EGFR signaling, which was mediated by NF-κB (p65). MCM8 interacted with DNA-replication-initiating factors-including EZH2, CDC6, and CDCA2-and influenced these factors to associate with chromatin. In addition, MCM8 knockdown increased the sensitivity of GSCs to radiation and TMZ treatments. Our findings suggest that MCM8, regulated by the EGFR pathway, maintains the clonogenic and tumorigenic potential of GSCs through interaction with DNA-replication-initiating factors; hence, MCM8 may represent a novel therapeutic target in GBMs.
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Glioma , OncogenesRESUMEN
RATIONALE: Tumor-to-tumor metastasis is a rare clinical phenomenon. Although meningioma is the most common intracranial recipient of cancer metastasis, only a few cases have been reported. We present a case of metastasis of lung adenocarcinoma into intracranial meningioma and review the published literature. PATIENT CONCERNS: A 70-year-old woman was admitted to our hospital for a 1-month history of headache and pain in her lower extremities. DIAGNOSIS: Brain and lumbar vertebral magnetic resonance imaging showed an intracranial space-occupying lesion in the right occipital region and spinal canal stenosis. Pulmonary computed tomography showed an irregular mass in the right upper lobe of the lung. The postoperative histological examination demonstrated adenocarcinoma metastasis to meningioma. INTERVENTION: The patient underwent right occipital craniotomy for tumor removal and lumbar spinal canal decompression. OUTCOMES: There were no initial abnormal conditions after the operation. However, the patient died suddenly 7 days after surgery. LESSONS: Tumor-to-meningioma metastasis is a rare but important phenomenon. According to previous reports, it is associated with rapid onset of symptoms and a poor prognosis. Histological examination is of great importance in diagnosis. The history and process of malignant carcinoma should be closely monitored.
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Adenocarcinoma/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/secundario , Anciano , Craneotomía , Diagnóstico Diferencial , Femenino , Cefalea/etiología , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/secundario , Meningioma/complicaciones , Meningioma/diagnóstico por imagen , Meningioma/secundario , Metástasis de la Neoplasia , Lóbulo OccipitalRESUMEN
BACKGROUND: Deregulation of the nuclear factor of activated T cell (NFAT) pathway has been reported in several human cancers. Particularly, NFAT2 is involved in the malignant transformation of tumor cells and is identified as an oncogene. However, the role of NFAT2 in glioblastoma (GBM) is largely unknown. METHODS: The expression and prognostic value of NFAT2 were examined in the databases of the Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas (TCGA) and clinical samples. The functional effects of silencing or overexpression of NFAT2 were evaluated in glioma stem cell (GSC) viability, invasion, and self-renewal in vitro and in tumorigenicity in vivo. The downstream target of NFAT2 was investigated. RESULTS: High NFAT2 expression was significantly associated with mesenchymal (MES) subtype and recurrent GBM and predicted poor survival. NFAT2 silencing inhibited the invasion and clonogenicity of MES GSC-enriched spheres in vitro and in vivo. NFAT2 overexpression promoted tumor growth and MES differentiation of GSCs. A TCGA database search showed that histone deacetylase 1 (HDAC1) expression was significantly correlated with that of NFAT2. NFAT2 regulates the transcriptional activity of HDAC1. Rescue of HDAC1 in NFAT2-knockdown GSCs partially restored tumor growth and MES phenotype. Loss of NFAT2 and HDAC1 expression resulted in hyperacetylation of nuclear factor-kappaB (NF-κB), which inhibits NF-κB-dependent transcriptional activity. CONCLUSION: Our findings suggest that the NFAT2-HDAC1 pathway might play an important role in the maintenance of the malignant phenotype and promote MES transition in GSCs, which provide potential molecular targets for the treatment of GBMs.
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Neoplasias Encefálicas/patología , Glioblastoma/patología , Histona Desacetilasa 1/metabolismo , Factores de Transcripción NFATC/metabolismo , Células Madre Neoplásicas/patología , Animales , Neoplasias Encefálicas/metabolismo , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Glioblastoma/metabolismo , Xenoinjertos , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Fenotipo , Transducción de Señal/fisiologíaRESUMEN
Background: Glioblastoma (GBM) is highly proliferative and resistant to radio-chemotherapy. Loss of tumor suppressor gene TP53 function frequently occurs at protein level in GBMs. This inhibition is often mediated by other components within the p53 signaling axis, including MDM2, whose binding protein (MTBP) plays an important role in the regulation of MDM2 and p53 activity. We investigated the role of MTBP in the biology of TP53-wildtype (TP53wt) GBMs. Methods: MTBP expression was examined in TCGA and REMBRANDT datasets. MTBP was silenced or overexpressed in TP53wt GBM cells and glioma stem cells (GSCs). The effects on cell viability, apoptosis, and clonogenicity were assessed. The transcriptional regulation of MTBP was investigated. Results: Upregulation of MTBP was correlated with the Classical molecular subtype, and it predicted poor survival. In TP53wt GBM cells, the protein levels of MTBP were positively associated with those of MDM2 but negatively correlated with those of p53. MTBP knockdown promoted apoptosis and inhibited clonogenicity, while overexpression of this protein enhanced tumorigenicity in vitro and in vivo. The pro-survival effect of MTBP depended on the activity of MDM2 and p53. MTBP was transcriptionally regulated by c-myc, thereby forming a positive regulatory loop. Finally, MTBP silencing increased the sensitivity of TP53wt GSCs to radiation and TMZ treatment in vitro and in vivo. Conclusion: MTBP regulates the cell survival and treatment sensitivity of TP53wt GBMs through MDM2-dependent post-translational modification of p53. MTBP-targeting treatments are potentially useful in increasing patients' survival.
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Proteínas Portadoras/metabolismo , Glioblastoma/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antineoplásicos Alquilantes/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/efectos de la radiación , Western Blotting , Proteínas Portadoras/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Supervivencia Celular/efectos de la radiación , Femenino , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/radioterapia , Glioma/genética , Glioma/metabolismo , Humanos , Inmunohistoquímica , Inmunoprecipitación , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/fisiología , Proteínas Proto-Oncogénicas c-mdm2/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Temozolomida/uso terapéutico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
PURPOSE: Intracranial meningiomas are relatively rare in young adults, and their specific clinical features remain unclear. The authors analyzed the clinical characteristics of intracranial meningioma in patients younger than 40 years. METHODS: Consecutive patients younger than 40 years with meningioma (n = 223) who underwent surgical treatment at our hospital from 2010 to 2018 were retrospectively reviewed. The study cases was further divided into a younger group (≤ 30 years old; n = 63) and an older group (31-40 years old; n = 160). The clinical information, radiological characteristics, intraoperative findings, and pathological outcomes were extracted from the patients' records and statistically analyzed. RESULTS: Intracranial meningioma is uncommon in patients younger than 40 years (8.6%). The study group's most common symptoms at presentation were headaches (46.7%), visual impairment (27.8%), limb weakness (20.6%), and epilepsy (13.5%). The mean tumor size was larger (51.47 ± 50.36 cm3) in the younger group than in the older group (22.94 ± 27.20 cm3). According to multivariate analyses, young age was an independent predictor of large tumor size, and large tumor size was significantly associated with peritumoral brain edema and intraoperative blood loss. CONCLUSION: Intracranial meningiomas in younger adult patients may have special complexity and perioperative risk due to large tumor sizes. Therefore, individualized treatment strategy is recommended, and the appropriate caution should be taken during surgery.
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Edema Encefálico/diagnóstico , Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Procedimientos Neuroquirúrgicos/efectos adversos , Hemorragia Posoperatoria/diagnóstico , Adolescente , Adulto , Factores de Edad , Edema Encefálico/etiología , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias Meníngeas/patología , Meningioma/patología , Hemorragia Posoperatoria/etiología , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
Glioma stem-like cells (GSC) promote tumor generation and progression. However, the mechanism of GSC induction or maintenance is largely unknown. We previously demonstrated that the calcium-responsive transcription factor nuclear factor of activated T cells-1 (NFAT1) is activated in glioblastomas and regulates the invasion of tumor cells. In this study, we further explored the role of NFAT1 in GSC. We found that NFAT1 expression was associated with an aggressive phenotype and predicted poor survival in gliomas. Compared with normal glioma cells, NFAT1 was upregulated in GSC. NFAT1 knockdown reduced GSC viability, invasion, and self-renewal in vitro and inhibited tumorigenesis in vivo, whereas NFAT1 overexpression enhanced the growth and invasion of GSCs. RNA sequencing showed that NFAT1 depletion was associated with reduced neurodevelopment protein 1-like 1 (NDEL1, a potential downstream target of NFAT1) expression, whereas NFAT1 overexpression induced NDEL1 expression. In addition, NFAT1 regulated the promoter activities of NDEL1, whereas rescue of NDEL1 in NFAT1-silenced GSC partially restored tumor growth and invasion. Upregulation of NFAT1-NDEL1 signaling elevated Erk activation, increased protein levels of stemness markers in GSC, and resulted in de-differentiation of normal neuronal cells and astrocytes. Our results indicate that NFAT1 controls the growth and invasion of GSC partially through regulation of NDEL1. Targeting the NFAT1-NDEL1 axis therefore might be of potential benefit in the treatment of patients with glioma. SIGNIFICANCE: NFAT1 controls the growth and invasion of GSCs, partially by regulating NDEL1. Targeting the NFAT1-NDEL1 axis might provide opportunities in treating patients with glioma.