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Abstract Background Chordoma is a rare malignant bone tumor exhibiting poor survival and prognosis. Hence, it is crucial to develop a convenient and effective prognostic classification method for the rehabilitation and management of patients with chordoma. In this study, we combined DNA methylation profiles and magnetic resonance imaging (MRI) images to generate a radiogenomic signature to assess its effectiveness for prognosis classification in patients with skull base chordoma. Results DNA methylation profiles from chordoma tissue samples of 40 patients were factorized into eight DNA methylation signatures. Among them, Signature 4 was identified as the prognosis-specific signature. Based on the Signature 4 loading values, the patients were categorized into low-signature (LLG) and high-signature (HLG) loading groups. HLG patients had higher progression-free survival times than LLG patients. Combined analysis with external single-cell RNA-seq data revealed higher tumor cell proportions and lower natural killer cell proportions in the HLG than in the LLG. Additionally, 2,553 radiomic features were extracted from T1, T2, and enhanced T1 MRI images of the patients, and a radiogenomic signature comprising 14 radiomic features was developed. In a validation cohort of 122 patients, the radiogenomic signature successfully distinguished between the two groups (P = 0.027). Furthermore, the existence of Signature 4 was confirmed in an additional dataset of 14 patients. Conclusion We developed a prognostic radiogenomic signature using a radiogenomic classification method, which leverages MRI images to extract features that reflect the DNA methylation signature associated with prognosis, enabling the stratification of patients based on their prognostic risk. This method offers the advantages of being noninvasive and convenient.

Abstract Local progression of primary skull base chordoma (PSBC) is a sign of treatment failure. Predicting the postoperative progression of PSBC can aid in the development of individualized treatment plans to improve patients’ progression-free survival (PFS) after surgery. This study aimed to develop a multiparametric MRI-based fusion radiomic model (FRM) and clinicoradiomic model (CRM) via radiomic and clinical analysis and to explore their validity in predicting postoperative progression in PSBC patients before surgery. In this retrospective study, a total of 129 patients with PSBC from our institution, including 57 patients with progression, were enrolled and randomized to the training set (TS) or the validation set (VS) at a 2:1 ratio. Radiomic features were extracted and dimensionally reduced from 3.0 T/axial T2-weighted imaging (T2WI), T1-weighted imaging (T1WI) and contrast-enhanced T1-weighted imaging (CE-T1WI) sequences for each patient, and the features were used for radiomic analysis. Univariate and multivariate Cox regression analyses were used to screen for key clinical factors. We constructed models on the basis of multivariate logistic regression analysis. Receiver operating characteristic (ROC) curve, calibration curve, and decision curve analyses were performed to evaluate the performance of the clinical model (CM), FRM and CRM. Through analysis, we found that blood supply was the only significantly different clinical factor in the CM. For the FRM, the area under the receiver operating characteristic curve (AUC) of the TS was 0.925, and the calibration curves were consistent across the TS. In the CRM, the AUC of the TS was 0.929, the calibration curve analysis was consistent for both the TS and the VS, and the DCA showed that the net benefit was greater at a threshold probability of > 0% for both the TS and the VS. Our proposed FRM can help clinicians better predict PSBC progression preoperatively, and the use of the CRM can lead to the development of more appropriate protocols to improve patients’ PFS after surgery.

Background Pulmonary hypertension is a rare, progressive disorder that can lead to right ventricular hypertrophy, right heart failure, and even sudden death. N6‐methyladenosine modification and the main methyltransferase that mediates it, methyltransferase‐like (METTL) 3, exert important effects on many biological and pathophysiological processes. However, the role of METTL3 in pyroptosis remains unclear. Methods and Results Here, we characterized the role of METTL3 and the underlying cellular and molecular mechanisms of pyroptosis, which is involved in pulmonary hypertension. METTL3 was downregulated in a pulmonary hypertension mouse model and in hypoxia‐exposed pulmonary artery smooth muscle cell. The small interfering RNA–induced silencing of METTL3 decreased the m6A methylation levels and promoted pulmonary artery smooth muscle cell pyroptosis, mimicking the effects of hypoxia. In contrast, overexpression of METTL3 suppressed hypoxia‐induced pulmonary artery smooth muscle cell pyroptosis. Mechanistically, we identified the phosphate and tension homology deleted on chromosome 10 (PTEN) gene as a target of METTL3‐mediated m6A modification, and methylated phosphate and tension homology deleted on chromosome 10 mRNA was subsequently recognized by the m6A “reader” protein insulin‐like growth factor 2 mRNA‐binding protein 2, which directly bound to the m6A site on phosphate and tension homology deleted on chromosome 10 mRNA and enhanced its stability. Conclusions These results identify a new signaling pathway, the METTL3/phosphate and tension homology deleted on chromosome 10/insulin‐like growth factor 2 mRNA‐binding protein 2 axis, that participates in the regulation of hypoxia‐induced pyroptosis.

Abstract Purpose The main objective is to quantify the lens nuclear opacity using spectral-domain optical coherence tomography (SD-OCT) and to evaluate its association with Lens Opacities Classification System III (LOCS-III) system, lens thickness (LT), and surgical parameters. The secondary objective is to assess the diagnostic model performance for hard nuclear cataract. Methods This study included 70 eyes of 57 adults with cataract, with 49 (70%) and 21 (30%) in training and validation cohort, respectively. Correlations of the average nuclear density (AND) /maximum nuclear density (MND) with LOCS-III scores, LT, and surgical parameters were analyzed. Univariate and multivariate logistic regression analysis, receiver operating characteristic curves and calibration curves were performed for the diagnostic of hard nuclear cataract. Results The pre-operative uncorrected distance visual acuity (UDVA), intraocular pressure (IOP), mean axial length (AL), and LT were 1.20 ± 0.47 log MAR, 15.50 ± 2.87 mmHg, 27.34 ± 3.77 mm and 4.32 ± 0.45 mm, respectively. The average nuclear opalescence (NO) and nuclear colour (NC) scores were 3.61 ± 0.94 and 3.50 ± 0.91 (ranging from 1.00 to 6.90), respectively. The average AND and MND were 137.94 ± 17.01 and 230.01 ± 8.91, respectively. NC and NO scores both significantly correlated with the AND (rNC = 0.733, p = 0.000; rNO = 0.755, p = 0.000) and MND (rNC = 0.643, p = 0.000; rNO = 0.634, p = 0.000). In the training cohort, the area under the curve (AUC) of the model was 0.769 (P

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Abstract Background Analyzing meningioma of distinct pathological types at the single-cell level can provide new and valuable insights into the specific biological mechanisms of each cellular subpopulation, as well as their vital interplay within the tumor microenvironment. Methods We recruited patients diagnosed with four distinct types of meningioma and performed single-cell RNA sequencing on their tumor samples, concurrently analyzing a publicly available dataset for comparison. Next, we separated the cells into discrete clusters and identified their unique identities. Using pseudotime analysis, we demonstrated cellular differentiation and dynamics. To investigate biological function, we employed weighted gene co-expression network analysis, gene regulatory network, and gene set enrichment analysis. Additionally, we conducted cell–cell communication analyses to characterize interactions among different clusters and validated a crucial interaction using multiple immunofluorescence staining. Results The single-cell transcriptomic profiles for five meningioma of different pathological types demonstrated that neoplastic cells exhibited high inter-sample heterogeneity and diverse biological functions featured by metabolic regulation. A small cluster of neoplastic cells (N5 cluster,

TiB2/Ti(C,N) cermet was prepared by reactive spark plasma sintering from the Co-Ti-BN-C-carbide powder compact. The formation mechanism and shrinkage behavior were studied. Results showed that Ti(C,N) was produced by the diffusion of C atoms into a preformed TiN. TiN-forming reaction was exothermic, which would lead to the occurrence of deep macropores and an abnormal expansion phenomenon. With increasing temperature, the macropores became increasingly shallow. Eventually, they disappeared through the viscous flow and dissolution-reaction-precipitation mechanisms. This behavior was primarily responsible for sintering densification. Among various carbide additives, TaC displayed the optimal effect. The hardness and fracture toughness of cermet reached 1917.4 HV and 8.81 MPa m−1/2. The reason was the formation of a black core/gray rim structure by the diffusion of heavy elements in liquid into the Ti(C,N). Results from the present work could offer a deep understanding of reactive spark plasma sintering, and would be beneficial for the development of Ti(C,N)-based cermet.

ABSTRACT Fungicides are an effective way to control gray mold of grapes, but the pathogen Botrytis cinerea can develop resistance, overcoming the effectiveness of a fungicide that is repeatedly applied. More importantly, the emergence of multidrug resistance (MDR) in the field, where multiple fungicides with different modes of action simultaneously lose their efficacies, is a significant concern. MDR is associated with ATP-binding cassette (ABC) transporters of the pathogen, and certain plant secondary metabolites (PSMs) stimulate the upregulation of ABC transporters, we hypothesized that the pathogen’s preadaptation to PSMs might contribute to MDR development. To test this in B. cinerea, ten PSMs, namely, resveratrol, reserpine, chalcone, flavanone, eugenol, farnesol, anethene, camptothecin, salicylic acid, and psoralen, were selected based on their association with ABC transporters involved in fungicide resistance. B. cinerea strain B05.10 was continuously transferred for 15 generations on potato dextrose agar amended with a PSM (PDAP), and sensitivities to PSMs and fungicides were examined on the 5th, 10th, and 15th generations. RNA was extracted from B. cinerea from the selected generations. After 15 generations of culture transfers, an up-regulation was observed in the expression of ABC transporter-encoding genes BcatrB, BcatrD, and BcatrK using quantitative polymerase chain reaction (qPCR). This upregulation was found to contribute to MDR of B. cinerea against two or more fungicides, among azoxystrobin, boscalid, fludioxonil, difenoconazole, prochloraz, and pyrimethanil. This finding was confirmed through genetic transformation. The decreased sensitivity of B. cinerea to fungicides was confirmed as a subsequent MDR phenotype after exposure to camptothecin, flavanone, and resveratrol. Besides, transcriptome analysis also revealed the upregulation of transcription factors related to ABC expression following resveratrol exposure. This suggests that PSMs contributed to inducing preadaptation of B. cinerea, leading to subsequent MDR.IMPORTANCEThe emergence of MDR in plant pathogens is a threat to plant disease management and leads to the use of excessive fungicides. Botrytis cinerea is of particular concern because its MDR has widely emerged in the field. Understanding its genesis is the first step for controlling MDR. In this study, the contribution of PSMs to MDR has been examined. Effective management of this pathogen in agroecosystems relies on a better understanding of how it copes with phytochemicals or fungicides.

Abstract Pattern formation caused by self-organization is a fascinating phenomenon that appears in biological, chemical, and physical systems. In ferroelectrics, although a variety of domain patterns have been reported at different scales and dimensions, the self-organization process of ferroelectric domains was rarely investigated. Here, in 0.72Pb(Mg1/3Nb2/3)O3−0.28PbTiO3 bulk crystals exposed to water, the self-organized formation process of domain structures is observed and reinforced by ultrasonic vibration. By combining experimental observations and theoretical analysis, we find that adsorbed H+/OH− ions on the sample surface act as screening charges to induce the coarsening of the ferroelectric domains. Meanwhile, interactions among dipoles determine the ordering of the domain configuration, while ultrasonic vibration reduces the barrier height for polarization switching. The process of domain evolution deviates from that of the non-conservative dynamic system, and instead fits a percolation model with a clear transition point. This work demonstrates the self-organization of ferroelectric domains induced by water, which is of value for understanding domain dynamics and for the development of high-performance ferroelectric materials.

Abstract Dispatchable energy storage system (ESS) plays a critical role in the smart grid through energy shift and power support. However, it exhibits different operational strategies and economic benefits in different application scenarios due to its inherent degradation behaviour. This paper aims to explore the technical and economic feasibility of the flexible traction power supply system (FTPSS) integrating ESS and renewable energy sources (RES) based on the traction load characteristics. First, a battery degradation model applicable in its frequent charging and discharging operating conditions is derived. Then this paper develops an operational‐sizing co‐optimization framework for the ESS in the FTPSS, where the operation decisions are made considering the degradation costs varying with the sizes and energy throughput. To solve this large‐scale non‐linear intertemporal decision‐making problem, an iterative method with a linear programming (LP) core is proposed to achieve the trade‐off between computational efficiency and accuracy. The results of the extensive comparative cases show that the proposed approach can achieve approximately 10% higher economic benefits than the existing bi‐level sizing strategies for FTPSS.

Summary: In biological systems, protein function depends on spatial and temporal changes known as protein dynamics, which can be probed by amide hydrogen/deuterium (H/D) exchange. Here, we present a protocol for determining protein dynamics by Fourier-transform infrared (FT-IR) spectroscopy. We describe steps for protein sample preparation and FT-IR spectra collection. We then detail procedures for spectra analysis. Applications include the effects of protein mutation or protein and metal ion or ligand interactions on the protein H/D exchange rate.For complete details on the use and execution of this protocol, please refer to Yu et al. (2013).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

ObjectivePrimary adult choroid plexus carcinomas (PACPCs) are extremely rare brain tumors. The existing literature primarily comprises case reports, which limits our understanding of this uncommon disease. This study aims to describe the clinical characteristics and prognosis of PACPCs, as well as to identify optimal treatment strategies.MethodsWe conducted a comprehensive analysis of clinical data from 7 patients with PACPCs who underwent surgical treatment at the Department of Neurosurgery, Beijing Tiantan Hospital, between March 2011 and March 2023. Additionally, a thorough search of the PubMed database was performed using the keywords “choroid plexus carcinoma” or “choroid plexus carcinomas” within the time frame of August 1975 to April 2023, which yielded a total of 28 identified cases. Subsequently, we evaluated risk factors for progression-free survival (PFS) and overall survival (OS) based on the pooled cases.ResultsThe pooled cohort, consisting of 7 cases from our institution and 28 cases from the literature, included 20 males and 15 females with a mean age of 44.3 ± 14.7 years (range: 21-73 years). Gross-total resection (GTR) and non-GTR were achieved in 22 (62.9%) and 13 (37.1%) patients, respectively. Radiotherapy and chemotherapy were administered to 29 (90.6%) and 13 (40.6%) patients, respectively. After a mean follow-up of 21.0 ± 26.7 months (range: 2-132 months), 18 patients were alive, and 11 patients had died. The multivariate Cox regression model demonstrated that non-GTR (HR 5.262, 95% CI 1.350-20.516, p=0.017) was a negative prognostic factor for OS. However, we did not find any risk factors for PFS.ConclusionComplete surgical resection should be considered as the primary treatment approach for this rare disease. Chemotherapy and radiotherapy appear to have limited effectiveness in treating this condition. Further research with large cohorts is needed to validate our conclusions.

APSES (Asm1p, Phd1p, Sok2p, Efg1p, and StuAp) family transcription factors play crucial roles in various biological processes of fungi, however, their functional characterization in phytopathogenic fungi is limited. In this study, we explored the role of SsStuA, a typical APSES transcription factor, in the regulation of cell wall integrity (CWI), sclerotia formation and pathogenicity of Sclerotinia sclerotiorum, which is a globally important plant pathogenic fungus. A deficiency of SsStuA led to abnormal phosphorylation level of SsSmk3, the key gene SsAGM1 for UDP-GlcNAc synthesis was unable to respond to cell wall stress, and decreased tolerance to tebuconazole. In addition, ΔSsStuA was unable to form sclerotia but produced more compound appressoria. Nevertheless, the virulence of ΔSsStuA was significantly reduced due to the deficiency of the invasive hyphal growth and increased susceptibility to hydrogen peroxide. We also revealed that SsStuA could bind to the promoter of catalase family genes which regulate the expression of catalase genes. Furthermore, the level of reactive oxygen species (ROS) accumulation was found to be increased in ΔSsStuA. In summary, SsStuA, as a core transcription factor involved in the CWI pathway and ROS response, is required for vegetative growth, sclerotia formation, fungicide tolerance and the full virulence of S. sclerotiorum.

The necrotrophic pathogen Botrytis cinerea infects a broad range of plant hosts and causes substantial economic losses to many crops. Although resistance to procymidone has been observed in the field, it remains uncertain why procymidone is usually involved in multidrug resistance (MDR) together with other fungicides. Nine mutants derived from the B. cinerea strain B05.10 through procymidone domestication exhibited high resistance factors (RFs) against both procymidone and fludioxonil. However, the fitness of the mutants was reduced compared to their parental strain, showing non-sporulation and moderate virulence. Furthermore, the RFs of these mutants to other fungicides, such as azoxystrobin, fluazinam, difenoconazole, and pyrimethanil, ranged from 10 to 151, indicating the occurrence of MDR. Transcriptive expression analysis using the quantitative polymerase chain reaction (qPCR) revealed that the mutants overexpressed ABC transporter genes, ranging from 2 to 93.7-fold. These mutants carried single-point mutations W647X, R96X, and Q751X within BcBos1 by DNA sequencing. These alterations in BcBos1 conferred resistance to procymidone and other fungicides in the mutants. Molecular docking analysis suggested distinct interactions between procymidone and Bos1 in the B. cinerea standard strain B05.10 or the resistant mutants, suggesting a higher affinity of the former towards binding with the fungicide. This study provides a comprehensive understanding of the biological characteristics of the resistant mutants and conducts an initial investigation into its fungicide resistance traits, providing a reference for understanding the causes of multidrug resistance of B. cinerea in the field.

Pyroptosis is involved in pulmonary hypertension (PH); however, whether this process is regulated by long non-coding RNAs (lncRNAs) is unclear. Some lncRNAs encode peptides; therefore, whether the regulation of pyroptosis in PH depends on lncRNAs themselves or their encoded peptides needs to be explored. We aimed to characterize the role of the peptide RPS4XL encoded by lnc-Rps4l and its regulatory mechanisms during pyroptosis in PH. Transgenic mice overexpression of lnc-Rps4l was established to rescue the inhibition of hypoxia-induced pyroptosis in pulmonary artery smooth muscle cells (PASMCs). An adeno-associated virus 9 construct with a mutation in the open reading frame of lnc-Rps4l was used to verify that it could inhibit hypoxia-induced PASMCs pyroptosis through its encoded peptide RPS4XL. Glutathione S-transferase (GST) pull-down assays revealed that RPS4XL bound to HSC70, and microscale thermophoresis (MST) was performed to determine the HSC70 domain that interacted with RPS4XL. Through glycosylation site mutation, we confirmed that RPS4XL inhibited hypoxia-induced PASMCs pyroptosis by regulating HSC70 glycosylation. Our results showed that RPS4XL inhibits pyroptosis in a PH mouse model and hypoxic PASMCs by regulating HSC70 glycosylation. These results further clarify the important mechanism of vascular remodeling in PH pathology.

PurposeHigh grade pleomorphic xanthoastrocytomas (HGPXAs) are very rare and their management and prognostic outcomes remain unclear. To better understand the disease, we aimed to evaluate the risk factors for progression-free survival (PFS) and overall survival (OS), and propose a treatment protocol based on cases from our institute and cases from the literature.MethodsThe authors reviewed the clinical data of 26 patients with HGPXAs who underwent surgical treatment in Department of Neurosurgery of Beijing Tiantan Hospital between August 2014 and September 2021. We also searched the PubMed database using the keywords “anaplastic” combined with “pleomorphic xanthoastrocytoma(s)” between January 1997 and October 2022. Risk factors for PFS and OS were evaluated in the pooled cases.ResultsThe authors’ cohort included 11 males and 15 females with a mean age of 36.7 ± 20.3 years (range: 5.5-71 years). Gross-total resection (GTR) and non-GTR were achieved in 17 (65.4%) and 9 (34.6%) patients, respectively. Radiotherapy and chemotherapy were administered to 22 and 20 patients, respectively. After a mean follow-up of 20.5 ± 21.2 months (range: 0.5-78.1 months), 7 patients suffered tumor recurrence and 6 patients died with a mean OS time of 19.4 ± 10.8 months (range: 8-36 months). In the literature between January 1997 and October 2022, 56 cases of HGPXAs were identified in 29 males and 27 females with a mean age of 29.6 ± 19.6 years (range; 4-74 years). Among them, 24 (44.4%) patients achieved GTR. Radiotherapy and chemotherapy was administered to 31 (62%) patients and 23 (46%) patients, respectively. After a median follow-up of 31.4 ± 35.3 months (range: 0.75-144 months), the mortality and recurrence rates were 32.5% (13/40) and 70% (28/40), respectively. Multivariate Cox regression model demonstrated that non-GTR (HR 0.380, 95% CI 0.174-0.831, p=0.015), age≥30 (HR 2.620, 95% CI 1.183-5.804, p=0.018), no RT (HR 0.334,95% CI 0.150-0.744, p=0.007) and no CT (HR 0.422, 95% CI 0.184-0.967, p=0.042) were negative prognostic factors for PFS. Non-GTR (HR 0.126, 95% CI 0.037-0.422, p=0.001), secondary HGPXAs (HR 7.567, 95% CI 2.221-25.781, p=0.001), age≥30 (HR 3.568, 95% CI 1.190-10.694, p=0.023) and no RT (HR 0.223,95% CI 0.073-0.681, p=0.008) were risk factors for OS.Conclusion:High grade pleomorphic xanthoastrocytomas are very rare brain tumors. Children and younger adults have better clinical outcome than elderly patients. Secondary HGPXAs had worse OS than primary HGPXAs. Complete surgical excision plus RT and CT is recommended for this entity. The frequency of BRAF mutations in HGPXAs is 47.5% (19/40) in this study, however, we do not find the connections between BRAF mutations and clinical outcomes. Future studies with larger cohorts are necessary to verify our findings.

ObjectiveNeuroNavigation (NN) is a widely used intraoperative imaging guidance technique in neurosurgical operations; however, its value in brainstem glioma (BSG) surgery is inadequately reported and lacks objective proof. This study aims to investigate the applicational value of NN in BSG surgery.MethodA retrospective analysis was performed on 155 patients with brainstem gliomas who received craniotomy from May 2019 to January 2022 at Beijing Tiantan Hospital. Eighty-four (54.2%) patients received surgery with NN. Preoperative and postoperative cranial nerve dysfunctions, muscle strength, and Karnofsky (KPS) were evaluated. Patients’ radiological features, tumor volume, and extent of resection (EOR) were obtained from conventional MRI data. Patients’ follow-up data were also collected. Comparative analyses on these variables were made between the NN group and the non-NN group.ResultThe usage of NN is independently related to a higher EOR in diffuse intrinsic pontine glioma (DIPG) (p=0.005) and non-DIPG group (p

BackgroundDiffuse intrinsic pontine gliomas (DIPGs) are rare and fatal pediatric brainstem gliomas with no cure. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have been proven effective in treating glioblastoma (GBM) in preclinical studies. However, there are no relevant studies on the CAR-NK treatment for DIPG. Our study is the first to evaluate the anti-tumor activity and safety of GD2-CAR NK-92 cells treatment for DIPG.MethodsFive patient-derived DIPG cells and primary pontine neural progenitor cell (PPC) were used to access disialoganglioside GD2 expression. Cell killing activity of GD2-CAR NK-92 cells was analyzed by in vitro cytotoxicity assays. Two DIPG patient-derived xenograft models were established to detect the anti-tumor efficacy of GD2-CAR NK-92 cells in vivo.ResultsAmong the five patient-derived DIPG cells, four had high GD2 expression, and one had low GD2 expression. In in vitro assays, GD2-CAR NK-92 cells could effectively kill DIPG cells with high GD2 expression while having limited activity against DIPG cells with low GD2 expression. In in vivo assays, GD2-CAR NK-92 cells could inhibit tumor growth in TT150630 DIPG patient-derived xenograft mice (high GD2 expression) and prolong the overall survival of the mice. However, GD2-CAR NK-92 showed limited anti-tumor activity for TT190326DIPG patient-derived xenograft mice (low GD2 expression).ConclusionOur study demonstrates the potential and safety of GD2-CAR NK-92 cells for adoptive immunotherapy of DIPG. The safety and anti-tumor effect of this therapy need to be further demonstrated in future clinical trials.

Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors. Here, we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals. In blood, sperm, and muscle cells, we resolved three common types of mutational signatures. Signatures A and B represent clock-like mutational processes, and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles. Notably, signature C, characterized by C>T transitions at GpCpN sites, tends to be a feature of diverse normal tissues. Mutations of this type are likely to occur early during embryonic development, supported by their relatively high allelic frequencies, presence in multiple tissues, and decrease in occurrence with age. Almost none of the public datasets for tumors feature this signature, except for 19.6% of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway. Moreover, the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α. Thus, embryonic hypoxia may explain this novel signature across multiple normal tissues. Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites; and individuals’ genetic background may also influence their postzygotic mutation profiles.

The COVID-19 pandemic has highlighted the importance of materials and coatings for antiviral surfaces. Here, a comprehensive review is performed for natural and synthetic antiviral and virucidal materials, including a discussion of their underpinning mechanisms.

ObjectiveThis work aimed to examine the function of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in skull base chordoma (SBC) at the clinical and cellular levels.MethodsTotally 65 paraffin-embedded and 86 frozen specimens from 96 patients administered surgery were analyzed. Immunohistochemical staining and quantitative real-time polymerase chain reaction were performed, and the associations of PTEN expression with clinical features were assessed. At the cellular level, PTEN was knocked down by the siRNA approach in the UCH-1 cell line, and cell proliferation and invasion were detected by the CCK-8 and migration assays, respectively.ResultsAt the protein level, PTEN expression was increased in non-bone-invasive tumor samples in comparison with bone-invasive specimens (p = 0.025), and elevated in soft SBCs in comparison with hard tumors (p = 0.017). Increased PTEN protein expression was associated with decreased risk of tumor progression (p = 0.002; hazard ratio = 0.981, 95% confidence interval: 0.969–0.993). At the gene expression level, the cut-off value was set at 10.5 after ROC curve analysis, and SBC specimens were divided into two groups: PTEN high group, ΔCt value below 10.5; PTEN low group, ΔCt value above 10.5. In multivariate regression analysis of PFS, the risk of tumor progression was increased in PTEN low group tumors in comparison with PTEN high group SBCs (p = 0.006). In the CCK-8 assay, in comparison with control cells, PTEN knockdown cells had increased absorbance, suggesting elevated cell proliferation rate. In the invasion assay, the number of tumor cells penetrating into the lower chamber was significantly increased in the PTEN knockdown group compared with control cells.ConclusionsDecreased PTEN expression in SBC, at the protein and gene levels, is associated with reduced PFS. PTEN knockdown in chordoma cells led to enhanced proliferation and invasiveness.

Emerging evidence has suggested that circular RNAs (circRNAs) are involved in multiple physiological processes and participate in a variety of human diseases. However, the underlying biological function of circRNAs in pulmonary hypertension (PH) is still ambiguous. Herein, we investigated the implication and regulatory effect of a typical circRNA, CDR1as, in the pathological process of vascular calcification in PH. Human pulmonary artery smooth muscle cell (HPASMC) calcification was analyzed by western blotting, immunofluorescence, alizarin red S staining, alkaline phosphatase activity analysis, and calcium deposition quantification. CDR1as targets were identified by bioinformatics analysis and validated by dual-luciferase reporter and RNA antisense purification assays. We identified that CDR1as was upregulated in hypoxic conditions and promoted a phenotypic switch of HPASMCs from a contractile to an osteogenic phenotype. Moreover, microRNA (miR)-7-5p was shown to be a target of CDR1as, and calcium/calmodulin-dependent kinase II-delta (CAMK2D) and calponin 3 (CNN3) were suggested to be the putative target genes and regulated by CDR1as/miR-7-5p. The results showed that the CDR1as/miR-7-5p/CNN3 and CAMK2D regulatory axis mediates HPASMC osteoblastic differentiation and calcification induced by hypoxia. This evidence reveals an approach to the treatment of PH.

Brainstem gliomas are heterogenous in terms of clinical outcome and disease etiology. Here, the authors present a genetic and epigenetic landscape of brainstem gliomas, finding distinct epigenetic clusters associated with unique genetic and clinical profiles.

Abstract In this paper, we study some nonlinear second order multi-point boundary value problems. We first give a lemma about the characteristic values of the corresponding linear operator. Then, by fixed point theorems in the recent existing literature, we obtain the existence of multiple solutions for these nonlinear second order multi-point boundary value problems, including two positive solutions, two negative solutions, and one sign-changing solution.

The necrotrophic fungus Sclerotinia sclerotiorum is a devastating pathogen. S. sclerotiorum can cause Sclerotinia stem rot in more than 600 species of plants, which results in serious economic losses every year. Chitin is one of the most important polysaccharides in fungal cell walls. Chitin and β-Glucan form a scaffold that wraps around the cell and determines the vegetative growth and pathogenicity of pathogens. UDP-GlcNAc is a direct precursor of chitin synthesis. During the synthesis of UDP-GlcNAc, the conversion of GlcNAc-6P to GlcNAc-1P that is catalyzed by AGM1 (N-acetylglucosamine-phosphate mutase) is a key step. However, the significance and role of AGM1 in phytopathogenic fungus are unclear. We identified a cytoplasm-localized SsAGM1 in S. sclerotiorum, which is homologous to AGM1 of Saccharomyces cerevisiae. We utilized RNA interference (RNAi) and overexpression to characterize the function of SsAGM1 in S. sclerotiorum. After reducing the expression of SsAGM1, the contents of chitin and UDP-GlcNAc decreased significantly. Concomitantly, the gene-silenced transformants of SsAGM1 slowed vegetative growth and, importantly, lost the ability to produce sclerotia and infection cushion; it also lost virulence, even on wounded leaves. In addition, SsAGM1 was also involved in the response to osmotic stress and inhibitors of cell wall synthesis. Our results revealed the function of SsAGM1 in the growth, development, stress response, and pathogenicity in S. sclerotiorum.

BackgroundAccurate preoperative differentiation of intracranial hemangiopericytoma and angiomatous meningioma can greatly assist operation plan making and prognosis prediction. In this study, a clini-radiomic model combining radiomic and clinical features was used to distinguish intracranial hemangiopericytoma and hemangioma meningioma preoperatively.MethodsA total of 147 patients with intracranial hemangiopericytoma and 73 patients with angiomatous meningioma from the Tiantan Hospital were retrospectively reviewed and randomly assigned to training and validation sets. Radiomic features were extracted from MR images, the elastic net and recursive feature elimination algorithms were applied to select radiomic features for constructing a fusion radiomic model. Subsequently, multivariable logistic regression analysis was used to construct a clinical model, then a clini-radiomic model incorporating the fusion radiomic model and clinical features was constructed for individual predictions. The calibration, discriminating capacity, and clinical usefulness were also evaluated.ResultsSix significant radiomic features were selected to construct a fusion radiomic model that achieved an area under the curve (AUC) value of 0.900 and 0.900 in the training and validation sets, respectively. A clini-radiomic model that incorporated the radiomic model and clinical features was constructed and showed good discrimination and calibration, with an AUC of 0.920 in the training set and 0.910 in the validation set. The analysis of the decision curve showed that the fusion radiomic model and clini-radiomic model were clinically useful.ConclusionsOur clini-radiomic model showed great performance and high sensitivity in the differential diagnosis of intracranial hemangiopericytoma and angiomatous meningioma, and could contribute to non-invasive development of individualized diagnosis and treatment for these patients.

Objectives: To explore the effectiveness and safety of the combined application of sodium fluorescein and neuronavigation techniques in the resection of brain gliomas in different locations and patients of different ages.Methods: Fifty clinical cases of brain gliomas treated at the Department of Neurosurgery of Beijing Tiantan Hospital were collected from March 2014 to March 2019. These cases were divided into a supratentorial group (24 cases) and a brainstem group (26 cases) based on location and an adult group (28 cases) and a pediatric group (22 cases) based on age. Fluorescein-guided surgery was performed: the adult group received 5 mg/kg sodium fluorescein before opening the dura, while the pediatric group received 2.5 mg/kg during resection. Tumor visualization was evaluated by the enhancement of yellow fluorescein and considered “satisfactory” if the illumination demarcated the tumor boundary. Additionally, the consistency between fluorescein and neuronavigation was analyzed. The Karnofsky performance score (KPS) of all patients was recorded and assessed at admission, discharge, and the 6-month follow-up.Results: In the 28 adult cases, 4 were unsatisfactory, while in the 22 pediatric cases, 2 were unsatisfactory; in 7 cases, there was an inconsistency between yellow fluorescein enhancement and neuronavigation, 6 were in the supratentorial group, and 1 was in the brainstem group. Statistical analysis showed no significant differences in the satisfactory rate between the adult and pediatric groups (P = 0.575), whereas there were significant differences inconsistency between the supratentorial group and brainstem group (P = 0.031). The mean KPS at admission was between 70 and 100, which was not significantly different from that at discharge (P = 0.839), but the KPS at the 6-month follow-up was significantly higher than that at admission (P = 0.041).Conclusions: The consistency between sodium fluorescein and the neuronavigation system was higher in the brainstem group than in the supratentorial group; a half dose of sodium fluorescein (2.5 mg/kg) was sufficient for pediatric patients. The combined utilization of sodium fluorescein and neuronavigation techniques may confer glioma patients the opportunity to obtain better clinical outcomes after surgery.

ObjectivePrimary squamous cell carcinomas (PSCCs) arising in intracranial epidermoid cysts (IECs) are very rare, and their management and prognostic factors remain unclear. This study aimed to enunciate the clinical features and suggest a treatment protocol based on cases from the literature and the cases from our institution.MethodsThe clinicoradiological data were obtained from nine patients with PSCCs arising in IECs, who underwent surgical treatment at Beijing Tiantan Hospital between July 2012 and June 2018. We also searched the PubMed database using the keywords “epidermoid cyst(s)” or “epidermoid tumor(s)” combined with “malignant” or “malignancy” or “intracranial” or “brain” or “squamous cell carcinoma” between 1960 and 2020. Risk factors for overall survival (OS) were evaluated in the pooled cohort.ResultsThe mean age of our cohort was 51.2 ± 8.3 years (range: 39–61 years), which included eight males and one female. Gross total resection (GTR) was achieved in three patients, while non-GTR was achieved in six patients. Radiotherapy was administered to five patients. After a median follow-up of 16.7 ± 21.6 months (range: 3–72 months), eight patients died with a mean OS time of 9.75 ± 6.6 months (range: 3–23 months). In the literature between 1965 and 2020, 45 cases of PSCCs arising in IECs were identified in 23 males and 22 females with a mean age of 55.2 ± 12.4 years. GTR, non-GTR, and biopsy were achieved in six (13.3%), 36 (80%), and three (6.7%) cases, respectively. After a mean follow-up of 12.7 ± 13.4 months (range: 0.33–60 months), 54.1% (20/37) patients died, and recurrence occurred in 53.6% (15/28) patients. A multivariate analysis demonstrated that postoperative radiotherapy (p = 0.002) was the only factor that favored OS. The Kaplan–Meier analysis showed that, compared with no radiotherapy (median survival time: 4 months), radiotherapy (median survival time: 24 months) had significantly prolonged OS (p = 0.0011), and GTR could not improve OS (p = 0.5826), compared with non-GTR. The 1-year OS of patients with or without radiotherapy was 72.5% or 18.2%, respectively.ConclusionMalignant transformation of IEC into PSCC was prevalent in elderly patients, with slight male predominance. GTR of previous benign IECs is recommended. For remnant benign IECs, close follow-up should be performed. Postoperative radiotherapy for PSCCs could bring survival benefit. GTR of these malignant intracranial tumors is difficult when they involve important brain structures. Future studies with larger cohorts are necessary to verify our findings.

Colorectal neoplasia differentially expressed (CRNDE) is an oncogenic long noncoding RNA (lncRNA) overexpressed in diverse malignancies. Here, we comprehensively analyze the prognostic value and molecular function of CRNDE in glioma. Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA), and single-cell RNA-sequencing data from the Tumor Immune Single-Cell Hub (TISCH) were analyzed. Kaplan–Meier survival analysis was applied to verify the prognostic value of CRNDE. Then, a nomogram based on multivariate Cox regression was established for individualized survival prediction. Subsequently, the expression characteristic and biological function of CRNDE were analyzed at the single-cell level. Lastly, the effects of CRNDE on the proliferation and invasion of glioma cell were explored in vitro. We discovered that CRNDE was a powerful marker for risk stratification of glioma patients. Regardless of the status of IDH and 1p/19q, CRNDE could effectively stratify patients’ prognosis. The nomogram that incorporated the CRNDE expression was proved to be a reliable tool for survival prediction. In addition, epithelial–mesenchymal transition may be the most important biological process regulated by CRNDE, which was identified at both the bulk and single-cell levels. Moreover, CRNDE knockdown significantly inhibited the proliferation and invasion of glioma cell. Overall, CRNDE is a vital oncogene and may be a valuable supplement to improve the clinical stratification of glioma.

Background: Prediction of brain invasion pre-operatively rather than postoperatively would contribute to the selection of surgical techniques, predicting meningioma grading and prognosis. Here, we aimed to predict the risk of brain invasion in meningioma pre-operatively using a nomogram by incorporating radiomic and clinical features. Methods: In this case-control study, 1728 patients from Beijing Tiantan Hospital (training cohort: n = 1070) and Lanzhou University Second Hospital (external validation cohort: n = 658) were diagnosed with meningiomas by histopathology. Radiomic features were extracted from the T1-weighted post-contrast and T2-weighted magnetic resonance imaging. The least absolute shrinkage and selection operator was used to select the most informative features of different modalities. The support vector machine algorithm was used to predict the risk of brain invasion. Furthermore, a nomogram was constructed by incorporating radiomics signature and clinical risk factors, and decision curve analysis was used to validate the clinical usefulness of the nomogram. Findings: Sixteen features were significantly correlated with brain invasion. The clinicoradiomic model derived from the fusing MRI sequences and sex resulted in the best discrimination ability for risk prediction of brain invasion, with areas under the curves (AUCs) of 0•857 (95% CI, 0•831–0•887) and 0•819 (95% CI, 0•775–0•863) and sensitivities of 72•8% and 90•1% in the training and validation cohorts, respectively. Interpretation: Our clinicoradiomic model showed good performance and high sensitivity for risk prediction of brain invasion in meningioma, and can be applied in patients with meningiomas. Funding: This work was supported by the National Natural Science Foundation of China (81772006, 81922040); the Youth Innovation Promotion Association CAS (grant numbers 2019136); special fund project for doctoral training program of Lanzhou University Second Hospital (grant numbers YJS-BD-33).

Meningiomas, as the most common primary tumor of the central nervous system, are known to harbor genomic aberrations that associate with clinical phenotypes. Here we performed genome-wide genotyping for cranial meningiomas in 383 Chinese patients and identified 9,821 copy-number variations (CNVs). Particularly, patients with diverse clinical features had distinct tumor CNV profiles. CNV burdens were greater in high-grade (WHO grade II and III) samples, recurrent lesions, large tumors (diameter >4.3 cm), and those collected from male patients. Nevertheless, the level of CNV burden did not relate to tumor locations, peritumoral brain edema, bone invasion, or multiple lesions. Overall, the most common tumor CNVs were the copy-number gain (CNG) at 22q11.1 and the copy-number losses (CNLs) at 22q13.2, 14q11.2, 1p34.3, and 1p31.3. Recurrent lesions were featured by the CNLs at 1p31.3, 6q22.31, 9p21.3, and 11p12, and high-grade samples had more CNVs at 4q13.3 and 6q22.31. Meanwhile, large tumors were more likely to have the CNVs at 1p31.3 and 1p34.3. Additionally, recurrence prediction indicated the CNLs at 4p16.3 (p = 0.009, hazard ratio = 5.69) and 10p11.22 (p = 0.037, hazard ratio = 4.53) were candidate independent risk factors.

Objective: To evaluate the diagnostic accuracy of routine blood examinations and Cerebrospinal Fluid (CSF) lactate level for Post-neurosurgical Bacterial Meningitis (PBM) at a large sample-size of post-neurosurgical patients. Methods: The diagnostic accuracies of routine blood examinations and CSF lactate level to distinguish between PAM and PBM were evaluated with the values of the Area Under the Curve of the Receiver Operating Characteristic (AUC-ROC) by retrospectively analyzing the datasets of post-neurosurgical patients in the clinical information databases. Results: The diagnostic accuracy of routine blood examinations was relatively low (AUC-ROC

Background: Accumulating evidence suggests that platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor(VEGF) play a role in the progression of pulmonary arterial hypertension (PAH).Since chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary arteries, which are histological hallmarks of PAH, we explored the role of the PDGF-BB/KLF4/VEGF signaling axis in the angiogenesis of pulmonary artery endothelial cells (PAECs). Methods: Adult male Wistar rats were used to study hypoxia-induced or monocrotaline (MCT)-induced right ventricular (RV) remodeling as well as systolic function and hemodynamics using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and RV vessels were performed. Results: The results revealed that both the PDGF receptor-tyrosine kinase inhibitor imatinib and the multi-targeted VEGF and PDGF receptor inhibit or sunitinib malate reversed hypoxia-induced increases in right ventricular systolic pressure (RVSP), right ventricular function and thickening of the medial walls. Mechanistically VEGF/VEGFR and PDGF/PDGFR formed a biological complex. We also showed that PDGF-BBincreasedKLF4 promoter activity transcriptionally activating VEGF expression, which regulates PAEC proliferation; migration; and the cell-cycle transition from G0/G1phase to S phase and G2/M-phase and eventually leads to PAEC angiogenesis Conclusion: Our study indicates that hypoxia-induced angiogenesis of PAECs is associated with increased levels of PDGF-BB/KLF4/VEGF, which contribute to pulmonary vascular remodeling. Overall, our study contributes to a better understanding of PAH pathogenesis.

Cerium oxide (CeO2) appears to be a promising candidate high-k dielectric material in GaAs-based metal-oxide-semiconductor field-effect transistors. The electronic properties of GaAs/CeO2 (001) heterojunctions are investigated by density functional theory. We determine the GaAs/CeO2 heterostructure from the initial adsorption of the Ga and As atoms on the CeO2 (001) surfaces. The surface formation energy indicates that oxygen or Ga atoms may replace Ce atoms at the Ce-terminated CeO2 surface, and Ce atoms may replace oxygen atoms at the O-terminated CeO2 surface. The band offsets, electronic density of states, and atomic charges are analyzed for the GaAs/CeO2 heterojunctions. The band offsets of the As-terminated GaAs/Ce-terminated CeO2 interface are suitable for the design of metal-oxide-semiconductor devices. The OCe defects induce a two-dimensional electron gas at the As-terminated GaAs/Ce-terminated CeO2 interface.

By using fixed point theorems with lattice structure, the existence of negative solution and sign-changing solution for some second-order multipoint boundary value problems is obtained.

Solidification microstructures of Cu-40 wt.% Pb alloy were examined under different undercooling degrees. The liquid phase separation mechanism in the systems with stable miscibility gaps mainly involved Ostwald ripening, Brownian motion, Marangoni migration, and Stokes motion. Stokes had little influence on the liquid phase separation in the early phase and played a leading role in the later period. The liquid phase separation mechanism of Cu-40 wt.% Pb hypermonotectic alloy was illustrated in detail.

The solidification microstructure of Fe-B eutectic alloy under high undercooling and high-density electric current pulse (ECP) was investigated with the technique of molten glass slag purification combined with cyclical superheating and the ECP treatment. The effects of high-density ECP on the undercooling of Fe-B eutectic alloy melt were analyzed by the DSC method. The analysis results showed that the solidification microstructure of Fe-B eutectic alloy under ECP was similar to that obtained by the high undercooling technique. The undercooling obtained under two experimental conditions was basically the same, proving that the high undercooling of the metallic melt could be realized by the ECP.

In this paper, the existence of positive solutions in terms of different values of two parameters for a system of conformable-type fractional differential equations with the p-Laplacian operator is obtained via Guo-Krasnosel’skii fixed point theorem.

A coupled macro-micro mathematical model of twin-roll casting was established in the study. The continuous solidification process of Al-10Mg aluminum alloys in front of the nip point was numerically simulated by the cellular automaton method and the solidification microstructure, dendritic grain radius, and secondary dendrite arm spacing were obtained through simulation to predict the mechanical property of wedge strips. In order to verify the reliability of the simulation results, the metallographic examination and tensile tests were performed with the as-cast specimens. The results showed that the gain size, the distribution characteristics of various grain regions, dendrite arm spacing, and the yield strengths obtained from simulation were consistent with experimental results.

We investigate in this paper the following second-order multipoint boundary value problem: -(Lφ)(t)=λf(t,φ(t)), 0≤t≤1, φ′0=0, φ1=∑i=1m-2βiφηi. Under some conditions, we obtain global structure of positive solution set of this boundary value problem and the behavior of positive solutions with respect to parameter λ by using global bifurcation method. We also obtain the infinite interval of parameter λ about the existence of positive solution.

Malignant transformation of intracranial epidermoid cyst (EC) is very rare, and when it does occur, the clinical course is aggressive. We present an unusual case of natural malignant transformation of an intracranial EC, without a history of surgery. A 61-year-old woman was diagnosed with an EC in the right cerebellopontine angle and prepontine cistern 6 years before the operation described in this report. Her neurological symptoms deteriorated in the 2 months prior to the present admission. Magnetic resonance imaging revealed an irregular, nodular enhanced lesion in the cerebellopontine angle, prepontine cistern, and temporoparietal lobe. Subtotal resection of the lesion was performed. Pathological examination revealed malignant transformation of the EC. The patient died on postoperative day 36 from brainstem infarction, chemical meningitis, and hydrocephalus. Spontaneous rupture of the EC could have contributed to the malignant transformation. This could have been avoided by early removal of the EC.

Although a bone tumor, significant differences in the extent of bone invasion exist in skull base chordoma, which directly affect the extent of surgical resection, and have an impact on its prognosis. However, the underlying mechanism of the phenomenon is not clearly understood. Therefore, we used an iTRAQ-based quantitative proteomics strategy to identify potential molecular signatures, and to find predictive markers of discrepancy in bone invasion of clivus chordoma. According to bone invasive classification criteria, 35 specimens of clivus chordoma were calssified to be either endophytic type (Type I) or exophytic type (Type II). An initial screening of six specimens of endophytic type and six of exophytic was performed, and 250 differentially expressed proteins were identified. Through the GO and IPA analysis, we found evidence that the expression of inflammatory activity-associated proteins up-regulated in endophytic type, whereas the expression of cell motility-associated proteins up-regulated in exophytic ones. Moreover, TGFβ1 and mTOR signal pathway seemed to be related with bone invasion. Thus, TGFβ1, PI3K, Akt, mTOR, and PTEN were validated in the following 23 samples by immune histochemistry and Western blot. The expression levels of TGFβ1 and PTEN were significantly lower in the endophytic type than in the exophytic ones. It was found that TGFβ1 may play an important role in its bone invasion. The mechanisms may be related with conducting an increased inflammatory cell response and a decline in cytoskeletal protein expression. PTEN is confirmed to be associated with the degree of bone invasion. The PI3K/AKT/mTOR signaling pathway might be associated with the bone invasion, but still needs a larger sample size to be verified These results, for the first time, not only demonstrate the biological changes that occur in different growth patterns from the perspective of proteomics, but also provide novel markers that may help to reveal the mechanisms behind clivus chordomas.