Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor. Conventional treatments have not achieved breakthroughs in improving survival. Therefore, novel molecular targets and ...biomarkers need to be identified. As signal transduction docks on the cell membrane, tetraspanins (TSPANs) are associated with various tumors; however, research on their role in GBM remains extremely scarce. Gene expression and clinicopathological characteristic data were obtained from GEPIA, CGGA, HPA, cBioPortal, and GSCA databases to analyze the mRNA and protein expression levels, prognostic value, clinical relevance, mutation status, and targeted drug sensitivity of TSPANs in GBM. Gene set enrichment analysis (GSEA), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for biological process enrichment. Data from TCGA and TCIA were used to construct the tumor immune microenvironment landscape of TSPANs. Different R software algorithms were used to analyze the immune score, immune cell infiltration, and immune checkpoint correlation. Univariate and multivariate analyses were performed for TSPAN4, which had the most significant predictive prognostic value, and a nomogram model was constructed to predict individual outcomes. The expression and function of TSPAN4 were verified in vitro. TSPAN3/4/6/11/12/18/23/24/25/26/27/28/29/30/31expressions were significantly upregulated in GBM, and TSPAN3/4/6/11/18/24/25/26/29/30 were strongly correlated with prognosis. The expression of multiple TSPANs significantly correlated with 1p/19q co-deletion status, IDH mutation status, recurrence, age, and tumor grade. GSEA and GO analyses revealed the potential contribution of TSPANs in cell adhesion and migration. Immune correlation analysis revealed that TSPANs are related to the formation of the GBM tumor microenvironment (TME) and may influence immunotherapy outcomes. TSPAN4 is an independent prognostic factor and TSPAN4 knockdown has been demonstrated to strongly inhibit glioma cell proliferation, invasion, and migration in vitro. We comprehensively elaborated the prognostic value and potential role of differentially expressed TSPANs in GBM, including molecules that scientists have previously overlooked. This study provides a novel and comprehensive perspective on the pathological mechanisms of GBM and the future direction of individualized tumor immunotherapy, which may be a critical link between GBM malignant progression and TME remodeling.
In this study, we developed a potential dual-function ligand targeting G-quadruplexes (G4s) by introducing a triazole rotor onto the dibenzoquinoxaline scaffold. This ligand not only had potential in ...high-contrast imaging of G4s either in vitro or in cellulo, but also proved to inhibit cancer cell growth as well as migration possibly through a G4-mediated action of mechanism. Altogether, this ligand had possibility to develop into a theranostic agent for cancer diagnosis and therapy in the future.
•A dual-function fluorescent ligand targeting G4s was developed.•The ligand showed high-contrast fluorescence upon interaction with G4s.•The ligand was able to label and stabilize the DNA G4s in live cells.
The heptamethine cyanine dyes are one kind of promising near-infrared (NIR) compounds, holding great potential in both diagnostic and therapeutic regions. Remolding such structures to realize ...detection of unclarified biotargets or interfering with them seems to be important in the field of chemical biology. In this study, we developed a fluorescent ligand (IR1) targeting mitochondrial G-quadruplexes (mitoG4s) by a slight variation on the typical NIR scaffold (IR780). This ligand could be applied for sensing mitoG4s by fluorescence, making it different from the unmodified dye whose fluorescence was quenched by mitoG4s. Then, IR1 was demonstrated to accumulate in the mitochondria through a mitochondrial membrane potential (MMP) dependent manner. Some of IR1 then bound to mitoG4s, causing mtDNA loss and mitochondrial dysfunction, which thereby triggered PANoptosis, including apoptosis, autophagy and pyroptosis. To the best of our knowledge, IR1 was the first NIR fluorescent ligand with emission centered at above 800 nm for mitoG4s, and the first example causing PANoptosis among the reported mitoG4-targeted ligands.
Background
Homeobox A (HOXA) family is involved in the development of malignancies as either tumor suppressors or oncogenes. However, their roles in glioblastoma (GBM) and clinical significance have ...not been fully elucidated.
Methods
HOXA mutation and expressions in pan-cancers were investigated using GSCA and Oncomine, which in GBM were validated by cBioPortal, Chinese Glioma Genome Atlas (CGGA), and The Cancer Genome Atlas (TCGA) datasets. Kaplan–Meier analyses were conducted to determine prognostic values of HOXAs at genetic and mRNA levels. Diagnostic roles of HOXAs in tumor classification were explored by GlioVis and R software. Independent prognostic HOXAs were identified using Cox survival analyses, the least absolute shrinkage and selection operator (LASSO) regression, quantitative real-time PCR, and immunohistochemical staining. A HOXAs-based nomogram survival prediction model was developed and evaluated using Kaplan–Meier analysis, time-dependent Area Under Curve, calibration plots, and Decision Curve Analysis in training and validation cohorts.
Results
HOXAs were highly mutated and overexpressed in pan-cancers, especially in CGGA and TCGA GBM datasets. Genetic alteration and mRNA expression of HOXAs were both found to be prognostic. Specific HOXAs could distinguish IDH mutation (HOXA1-7, HOXA9, HOXA13) and molecular GBM subtypes (HOXA1-2, HOXA9-11, HOXA13). HOXA1/2/3/10 were confirmed to be independent prognostic members, with high expressions validated in clinical GBM tissues. The HOXAs-based nomogram model exhibited good prediction performance and net benefits for patients in training and validation cohorts.
Conclusion
HOXA family has diagnostic values, and the HOXAs-based nomogram model is effective in survival prediction, providing a novel approach to support the treatment of GBM patients.
Existing theories and empirical studies have evidenced the association between bullying victimization and bullying perpetration. However, it is still unclear what factors mitigate or alter this risk ...linkage between bullying victimization and bullying perpetration to reduce bullying incidents. Guided by the social-ecological theory, this study used a longitudinal design to examine the moderating role of school climate in the association between bullying victimization and bullying perpetration at both the within-person and between-person levels among Chinese adolescents across a 1-year period. Participants included 2,997 Chinese adolescents (Mage = 14.9, 49.7% male) from 5 secondary schools. Results suggested that students who experienced high levels of bullying victimization were also involved in high levels of bullying perpetration over time (i.e., the positive within-person effect of bullying victimization on bullying perpetration). Results also showed that the between-person level of perceived school climate interacted with the within-person level of bullying victimization to predict the within-person level of bullying perpetration (i.e., cross-level effects). More specifically, the magnitude of the positive association between bullying victimization and bullying perpetration at the within-person level was mitigated among students with higher perceptions of school climate at the between-person level. Findings of the study highlighted the causal effect of bullying victimization on bullying perpetration and the buffering role of perceived school climate in the longitudinal association between bullying victimization and perpetration, which was consistent with the risk-buffering model but not the healthy context paradox hypothesis. Furthermore, the findings provided implications for bullying prevention and intervention services by using multitiered systems of support in bullying prevention efforts and highlights the need for promoting positive school climate.
The handheld ultrasound demonstrates clinical and economic value in combating COVID-19 based on interviews with frontline ultrasound physician and cardiologist as well as a national expert in medical ...ultrasound.
Notch receptors (Notch 1/2/3/4), the critical effectors of the Notch pathway, participate in the tumorigenesis and progression of many malignancies. However, the clinical roles of Notch receptors in ...primary glioblastoma (GBM) have not been fully elucidated.
The genetic alteration-related prognostic values of Notch receptors were determined in the GBM dataset from The Cancer Genome Atlas (TCGA). Two GBM datasets from TCGA and Chinese Glioma Genome Atlas (CGGA) were used to explore the differential expression between Notch receptors and IDH mutation status, and GBM subtypes. The biological functions of Notch Receptors were explored by Gene Ontology and KEGG analysis. The expression and prognostic significance of Notch receptors were determined in the TCGA and CGGA datasets and further validated in a clinical GBM cohort by immunostaining. A Notch3-based nomogram/predictive risk model was constructed in the TCGA dataset and validated in the CGGA dataset. The model performance was evaluated by receiver operating curves, calibration curves, and decision curve analyses. The Notch3-related phenotypes were analyzed via CancerSEA and TIMER. The proliferative role of Notch3 in GBM was validated in U251/U87 glioma cells by Western blot and immunostaining.
Notch receptors with genetic alterations were associated with poor survival of GBM patients. Notch receptors were all upregulated in GBM of TCGA and CGGA databases and closely related to the regulation of transcription, protein-lysine N-methyltransferase activity, lysine N-methyltransferase activity, and focal adhesion. Notch receptors were associated with Classical, Mesenchymal, and Proneural subtypes. Notch1 and Notch3 were closely correlated with IDH mutation status and G-CIMP subtype. Notch receptors displayed the differential expression at the protein level and Notch3 showed a prognostic significance in a clinical GBM cohort. Notch3 presented an independent prognostic role for primary GBM (IDH1 mutant/wildtype). A Notch3-based predictive risk model presented favorable accuracy, reliability, and net benefits for predicting the survival of GBM patients (IDH1 mutant/wildtype and IDH1 wildtype). Notch3 was closely related to immune infiltration (macrophages, CD4
T cells, and dendritic cells) and tumor proliferation.
Notch3-based nomogram served as a practical tool for anticipating the survival of GBM patients, which was related to immune-cell infiltration and tumor proliferation.
•First report of B. velezensis from F. hupehensis acting as a biocontrol agent.•B. velezensis D61-A showed a promising biocontrol agent for rice sheath blight.•B. velezensis D61-A has a broad ...antifungal spectrum, producing some lytic enzymes.
To find bacteria with potential biological control activity against the rice sheath blight pathogen, Rhizoctonia solani, bacterial endophytes from Fraxinus hupehensis were isolated, and screened for antifungal activity by dual culture assay. Over 30 bacterial isolates were obtained, and strains were examined for antifungal efficacy on detached leaves and in planta (rice), and for antagonistic mechanisms. Strain D61-A, tentatively identified as Bacillus velezensis based on sequence analyses of 16S rDNA and gyrB gene, showed the strongest inhibitory activity against R. solani with an inhibition rate of 80.1%, and was selected for further study. This strain produced cell-wall-degrading enzymes (protease and cellulase), siderophores and non-volatile metabolites. Crude protein extracted from D61-A byprecipitationwith ammonium sulfate exhibited strong inhibition (60.2%) of R. solani at 50 μg/mL. The strain gave 71% reduction in lesion length in a detached inoculated leaf assay. In the greenhouse and the field, the control efficacy of D61-A could reach 61.5% and 74.6%, respectively. To the best of our knowledge, this is the first report on screening and evaluation of endophytic biocontrol bacteria from F. hupehensis.
Introduction
Subarachnoid hemorrhage (SAH) is a severe hemorrhagic stroke with high mortality. However, there is a lack of clinical tools for predicting in-hospital mortality in clinical practice. ...LAR is a novel clinical marker that has demonstrated prognostic significance in a variety of diseases.
Methods
Critically ill patients diagnosed and SAH with their data in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and the eICU Collaborative Research Database (eICU-CRD) were included in our study. Multivariate logistic regression was utilized to establish the nomogram.
Results
A total of 244 patients with spontaneous SAH in the MIMIC-IV database were eligible for the study as a training set, and 83 patients in eICU-CRD were included for external validation. Data on clinical characteristics, laboratory parameters and outcomes were collected. Univariate and multivariate logistic regression analysis identified age (OR: 1.042,
P
-value: 0.003), LAR (OR: 2.592,
P
-value: 0.011), anion gap (OR: 1.134,
P
-value: 0.036) and APSIII (OR: 1.028,
P
-value: < 0.001) as independent predictors of in-hospital mortality and we developed a nomogram model based on these factors. The nomogram model incorporated with LAR, APSIII, age and anion gap demonstrated great discrimination and clinical utility both in the training set (accuracy: 77.5%, AUC: 0.811) and validation set (accuracy: 75.9%, AUC: 0.822).
Conclusion
LAR is closely associated with increased in-hospital mortality of patients with spontaneous SAH, which could serve as a novel clinical marker. The nomogram model combined with LAR, APSIII, age, and anion gap presents good predictive performance and clinical practicability.
Background
The chromobox family, a critical component of epigenetic regulators, participates in the tumorigenesis and progression of many malignancies. However, the roles of the CBX family members ...(CBXs) in glioblastoma (GBM) remain unclear.
Methods
The mRNA expression of CBXs was analyzed in tissues and cell lines by Oncomine and Cancer Cell Line Encyclopedia (CCLE). The differential expression of CBXs at the mRNA level was explored in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases with the “beeswarm” R package. The protein expression of CBXs in GBM was further examined on Human Protein Atlas (HPA). The correlations between CBXs and IDH mutation and between CBXs and GBM subtypes were investigated in the TCGA portal and CGGA database with the “survminer” R package. The alteration of CBXs and their prognostic value were further determined
via
the cBioPortal and CGGA database with the “survival” R package. The univariate and multivariate analyses were performed to screen out the independent prognostic roles of CBXs in the CGGA database. Cytoscape was used to visualize the functions and related pathways of CBXs in GBM. U251 and U87 glioma cells with gene intervention were used to validate the role of CBX7/8 in tumor proliferation and invasion. Proliferation/invasion-related markers were conducted by Western blot and immunostaining.
Results
CBXs presented significantly differential expressions in pan-cancers. CBX2/3/5/8 were upregulated, whereas CBX6/7 were downregulated at mRNA level in GBM of TCGA and CGGA databases. Similarly, high expression of CBX2/3/5 and low expression of CBX6/8 were further confirmed at the protein level in the HPA. CBX2/6/7 were positively correlated with IDH mutation and CBX1/2/4/5/8 were closely related to GBM subtypes. CBX7 and CBX8 presented the independent prognostic factors for GBM patient survival. GO and KEGG analyses indicated that CBXs were closely related to the histone H3-K36, PcG protein complex, ATPase, and Wnt pathway. The overexpression of CBX7 and underexpression of CBX8 significantly inhibited the proliferation and invasion of glioma cells
in vivo
and
in vitro
.
Conclusion
Our results suggested that CBX7 and CBX8 served as independent prognostic indicators that promoted the proliferation and invasion of glioma cells, providing a promising strategy for diagnosing and treating GBM.
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