HOXD9 is a potential prognostic biomarker involved in immune microenvironment of glioma.

BACKGROUND: Glioma is the prevailing malignant tumor affecting the brain and central nervous system, constituting over 80% of all malignant brain tumors. HOXD9 has been implicated in the development of glioma, but the specific mechanism of its influence on glioma pathogenesis remains incompletely understood. The purpose of this study was to investigate the role of HOXD9 in glioma and examine the changes in HOXD9 expression during the progression of glioma, thus contributing new insights into the pathogenesis of glioma. METHODS: Glioma samples from the Cancer Gene Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets were included in this study. Variations in HOXD9 expression in gliomas between different subgroups of multiple clinical characteristics were explored, and the expression was validated in glioma samples using qRT-PCR and western blotting. Next, the impact of HOXD9 on the prognosis of gliomas was explored by survival analysis, receiver operating characteristic curve, and nomogram plots. Subsequently, the association between HOXD9 and the tumor immune microenvironment was explored using the ssGSEA algorithm and the ESTIMATE algorithm. Then, immune-related pathways associated with HOXD9 were determined by differential express analysis and GSEA. Finally, HOXD9-related genomic alterations were identified. RESULTS: HOXD9 expression is upregulated and correlated with malignant properties in glioma. Similarly, our validation results showed significantly upregulated protein and mRNA levels of HOXD9 in glioma brain tissues. In addition, high HOXD9 expression was indicative of a poor prognosis for glioma patients. Additionally, elevated HOXD9 levels were associated with reduced tumor purity and higher levels of immune invasion. Finally, HOXD9 was significantly associated with genomic alterations. CONCLUSION: Overall, this study has unveiled a significant association between HOXD9 and the prognosis and survival of glioma patients. Our findings highlight the potential of HOXD9 as a prognostic biomarker, implicating its role in influencing the glioma immune microenvironment.

FLOT1, stabilized by WTAP/IGF2BP2 mediated N6-methyladenosine modification, predicts poor prognosis and promotes growth and invasion in gliomas.

The expression, function, and mechanism of FLOT1 (flotillin-1) remains unknown in gliomas. Here, the expression and clinical value of FLOT1 in gliomas was bioinformatically and experimentally analyzed via online omics data and local tissues. Moreover, the effects of FLOT1 depletion on cell proliferation and invasion were also detected. Besides, the underlying roles of N6-methyladenosine modification (m6A) in FLOT1 upregulation was further explored. The results demonstrated that FLOT1 was significantly upregulated in gliomas and positively correlated with advanced progression and poor prognosis of patients. FLOT1 silencing notably suppressed the cell proliferation and invasion in gliomas. The expression of WTAP and IGF2BP2was positively correlated with FLOT1 expression and served as the writer and reader of FLOT1 m6A, respectively, which stabilized FLOT1 mRNA and maintained its upregulation in gliomas. Lastly, ectopic expression of FLOT1 could notably restore the inhibitory effects caused by WTAP and IGF2BP2 depletion in glioma cells. Collectively, our results originally confirmed the upregulation and oncogenic roles of FLOT1, and revealed that WTAP/IGF2BP2 mediated m6A contributed to the upregulation of FLOT1 in gliomas, highlighting the promising application of WTAP/IGF2BP2/FLOT1 axis in target treatment of gliomas.

Extracellular vesicles released by glioma cells are decorated by Annexin A2 allowing for cellular uptake via heparan sulfate.

Extracellular vesicles (EVs) play a crucial role in regulating cell behavior by delivering their cargo to target cells. However, the mechanisms underlying EV-cell interactions are not well understood. Previous studies have shown that heparan sulfate (HS) on target cell surfaces can act as receptors for exosomes uptake, but the ligand for HS on EVs has not been identified. In this study, we isolated EVs from glioma cell lines and glioma patients and identified Annexin A2 (AnxA2) on EVs as a key HS-binding ligand and mediator of EV-cell interactions. Our findings suggest that HS plays a dual role in EV-cell interactions, where HS on EVs captures AnxA2, and on target cells, it acts as a receptor for AnxA2. Removal of HS from the EV surface inhibits EV-target cell interaction by releasing AnxA2. Furthermore, we found that AnxA2-mediated binding of EVs to vascular endothelial cells promotes angiogenesis, and that antibody against AnxA2 inhibited the ability of glioma-derived EVs to stimulate angiogenesis by reducing the uptake of EVs. Our study also suggests that the AnxA2-HS interaction may accelerate the glioma-derived EVs-mediated angiogenesis and that combining AnxA2 on glioma cells with HS on endothelial cells may effectively improve the prognosis evaluation of glioma patients.

GRN is a prognostic biomarker and correlated with immune infiltration in glioma: A study based on TCGA data.

Background: Among primary brain tumors, gliomas are associated with a poor prognosis and a median survival that varies depending on the tumor grade and subtype. As the most malignant form of glioma, glioblastoma (GBM) constitutes a significant health concern. Alteration in granulin(GRN) has been proved to be accountable for several diseases. However, the relationship between GRN and GBM remains unclear. We evaluated the role of GRN in GBM through The Cancer Genome Atlas (TCGA) database. Methods: First, we assessed the relationship between GRN and GBM through the GEPIA database. Next, the relationship between GRN and GBM prognosis was analyzed by logistic regression and multivariate cox methods. Using CIBERSORT and the GEPIA correlation module, we also investigated the link between GRN and immune infiltrates in cancer. Using the TCGA data, a gene set enrichment analysis (GSEA) was performed. We also employed Tumor Immune Estimation Resource (TIMER) to examine the data set of GRN expression and immune infiltration level in GBM and investigate the cumulative survival in GBM. We also validated tissues from GBM patients by Western blotting, RT-qPCR, and immunohistochemistry. Results: Increased GRN expression was shown to have a significant relationship to tumor grade in a univariate study utilizing logistic regression. Furthermore, multivariate analysis disclosed that GRN expression down-regulation is an independent predictive factor for a favorable outcome. GRN expression level positively correlates with the number of CD4+ T cells, neutrophils, macrophages, and dendritic cells (DCs) that infiltrate a GBM. The GSEA also found that the high GRN expression phenotype pathway was enriched for genes involved in immune response molecular mediator production, lymphocyte-mediated immunity, cytokine-mediated signaling pathway, leukocyte proliferation, cell chemotaxis, and CD4+ alpha beta T cell activation. Differentially enriched pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) include lysosome, apoptosis, primary immunodeficiency, chemokine signaling pathway, natural killer cell-mediated cytotoxicity, and B cell receptor signaling pathway. Validated result showed that GRN was upregulated in GBM tissues. These results suggested that GRN was a potential indicator for the status of GBM. Conclusion: GRN is a prognostic biomarker and correlated with immune infiltrates in GBM.

An Integrated Framework for Multi-State Driver Monitoring Using Heterogeneous Loss and Attention-Based Feature Decoupling.

Multi-state driver monitoring is a key technique in building human-centric intelligent driving systems. This paper presents an integrated visual-based multi-state driver monitoring framework that incorporates head rotation, gaze, blinking, and yawning. To solve the challenge of head pose and gaze estimation, this paper proposes a unified network architecture that tackles these estimations as soft classification tasks. A feature decoupling module was developed to decouple the extracted features from different axis domains. Furthermore, a cascade cross-entropy was designed to restrict large deviations during the training phase, which was combined with the other features to form a heterogeneous loss function. In addition, gaze consistency was used to optimize its estimation, which also informed the model architecture design of the gaze estimation task. Finally, the proposed method was verified on several widely used benchmark datasets. Comprehensive experiments were conducted to evaluate the proposed method and the experimental results showed that the proposed method could achieve a state-of-the-art performance compared to other methods.

Overexpression of Annexin A2 promotes proliferation by forming a Glypican 1/c-Myc positive feedback loop: prognostic significance in human glioma.

In order to set up a reliable prediction system for the tumor grade and prognosis in glioma patients, we clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. We found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, we utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expression of ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential "combination biomarker" for predicting prognosis of glioma patients.

FLOT2 upregulation promotes growth and invasion by interacting and stabilizing EphA2 in gliomas.

The expression and roles of FLOT2, especially for its underlying mechanism, in gliomas have been rarely revealed. In this study, upregulations of both FLOT2 and EphA2 in gliomas tissues were validated by immunohistochemistry (IHC) staining and Western blot. FLOT2 silencing notably inhibited the growth and invasion of gliomas cells. Simultaneously, FLOT2 depletion suppressed Akt and NF-κB activities, induced apoptosis, cell cycle arrest, and epithelial-mesenchymal transition (EMT) inhibition, demonstrated by expression alterations of key proteins of the above processes. Mechanistically, FLOT2 could maintain EphA2 stability viainteraction, and restoration of EphA2 could remarkably release the suppressive effects on gliomas cells induced by FLOT2 knockdown. Lastly, FLOT2 and EphA2, whose protein and mRNA levels are both positively correlated in gliomas, shows significant association with clinical characteristics like Ki67 intensity, p53 expression, and tumor stage in patients with gliomas. In conclusion, our results reveal the upregulation, oncogenic roles of FLOT2, and the corresponding underlying mechanism in gliomas, highlighting that the FLOT2-EphA2 axis is served as a promising therapeutic target for gliomas.

One-Port Electronic Detection Strategies for Improving Sensitivity in Piezoelectric Resonant Sensor Measurements.

This paper describes a one-port mechanical resonance detection scheme utilized on a piezoelectric thin film driven silicon circular diaphragm resonator and discusses the limitations to such an approach in degenerate mode mass detection sensors. The sensor utilizes degenerated vibration modes of a radial symmetrical microstructure thereby providing both a sense and reference mode allowing for minimization of environmental effects on performance. The circular diaphragm resonator was fabricated with thickness of 4.5 µm and diameter of 140 µm. A PZT thin film of 0.75 µm was patterned on the top surface for the purposes of excitation and vibration sensing. The device showed a resonant frequency of 5.8 MHz for the (1, 1) mode. An electronic interface circuit was designed to cancel out the large static and parasitic capacitance allowing for electrical detection of the mechanical vibration thereby enabling the frequency split between the sense and reference mode to be measured accurately. The extracted motional current, proportional to the vibration velocity, was fed back to the drive to effectively increase the Q factor, and therefore device sensitivity, by more than a factor of 8. A software phase-locked loop was implemented to automatically track the resonant frequencies to allow for faster and accurate resonance detection. Results showed that by utilizing the absolute mode frequencies as an indication of sensor temperature, the variation in sensor temperature due to the heating from the drive electronics was accounted for and led to an ultimate measurement sensitivity of 2.3 Hz.