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Immunotherapy, especially checkpoint inhibitors targeting PD-1 or PD-L1, has revolutionized cancer therapy. However, PD-1/PD-L1 inhibitors have not been investigated thoroughly in glioblastoma (GBM). Studies have shown that polymerase 1 and transcript release factor (PTRF/Cavin-1) has an immune-suppressive function in GBM. Thus, the relationship between PTRF and PD-L1 and their role in immune suppression requires further investigation in GBM. We used public databases and bioinformatics analysis to investigate the relationship between PTRF and PD-L1. We next confirmed the predicted relationship between PTRF and PD-L1 in primary GBM cell lines by using different experimental approaches. RIP-Seq, RIP, ChIP, and qRT-PCR were conducted to explore the molecular mechanism of PTRF in immunosuppression. We found that PTRF stabilizes lncRNA to induce NF-κB and PD-L1 and promotes immune evasion in GBM. PTRF was found to correlate with immunosuppression in the public GBM databases. PTRF increased the level of PD-L1 in primary cell lines from GBM patients. We carried out RIP-Seq of GBM cells and found that PTRF interacts with lncRNA and stabilizes its mRNA. PTRF also promoted the activity of NF-κB by suppressing UBXN1 expression and enhanced the transcription of PD-L1 through NF-κB activation. Finally, PTRF promoted immune evasion in GBM cells by regulating PD-1 binding and PD-L1 mediated T cell cytotoxicity. In summary, our study identified the PTRF- -PD-L1 axis as a novel immune therapeutic target in GBM.

In the field of ocean engineering, the variation of flow field during ship-to-ship (STS) interaction has been a hot topic. Noteworthy, the effect of vortex distribution on flow field characteristic variations during STS interaction remains insufficiently researched. This study modifies the RNG k-ε model using the OpenFOAM platform and verifies its reliability by comparing it with literature data. Subsequently, extended research is conducted to investigate the flow field characteristics of two different ship hull sections under different Reynolds numbers (Re=68,000 and Re=6800), analyzing velocity components, vortex distribution, and trends in pressure and turbulent kinetic energy fields relative to the vortex field. The research reveals that Re primarily governs changes in upstream and downstream flow fields, while in the gap field, the variation in flow field characteristics is more constrained by geometry and boundary conditions. This research provides a valuable reference for assessing flow field characteristics in STS interactions.

Background Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune‐escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR‐vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation. Methods Clinical GBM specimens were selected for single‐cell RNA sequencing and untargeted metabolomics analysis. A metabolism‐associated RTK‐fatty acid‐gene signature was constructed and verified. MK‐2206 and MK‐803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo. Results GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single‐cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl‐CoA synthetase short‐chain family member 3 (ACSS3), acyl‐CoA synthetase long‐chain family member 3 (ACSL3), and long‐chain fatty acid elongation‐related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF‐κB‐dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models. Conclusions Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR‐activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

Glioblastoma (GBM) displays a complex metabolic reprogramming in cancer cells. Adenosine triphosphate (ATP) is one of the central mediators of cell metabolism and signaling. GBM cells generate ATP by glycolysis and the tricarboxylic acid (TCA) cycle associated with oxidative phosphorylation (OXPHOS) through the breaking-down of pyruvate or fatty acids to meet the growing energy demand of cancer cells. Therefore, it's urgent to develop novel treatments targeting energy metabolism to hinder tumor cell proliferation in GBM. Non-targeted metabolomic profiling analysis was utilized to evaluate cell metabolic reprogramming using a small molecule inhibitor (SMI) EPIC-0412 treatment. Cellular oxygen consumption rate (OCR) and the total proton efflux rate (PER), as well as ATP concentration, were tracked to study metabolic responses to specifically targeted inhibitors, including EPIC-0412, arachidonyl trifluoromethyl ketone (AACOCF3), and 2 deoxy-D-glucose (2-DG). Cancer cell proliferation was assessed by CCK-8 measurements and colony formation assay. Additionally, flow cytometry, immunoblotting (IB), and immunofluorescence (IF) analyses were performed with GBM cells to understand their tumorigenic properties under treatments. Finally, the anticancer effects of this combination therapy were evaluated in the GBM mouse model by convection-enhanced delivery (CED). We found that SMI EPIC-0412 could effectively perturb the TCA cycle, which participated in the combination therapy of cytosolic phospholipase A2 (cPLA2)-inhibitor AACOCF3, and hexokinase II (HK2)-inhibitor 2-DG to disrupt the GBM energy metabolism for targeted metabolic treatments. ATP production was significantly declined in glioma cells when treated with monotherapy (EPIC-0412 or AACOCF3), dual therapy (EPIC-0412 + AACOCF3), or triple therapy (EPIC-0412 + AACOCF3 +2-DG) regimen. Our experiments revealed that these therapies hindered glioma cell proliferation and growth, leading to the reduction in ATP production and G0/G1 cell cycle arrest. We demonstrated that the combination therapy effectively extended the survival of cerebral tumor-bearing mice. Our findings indicate that the TCA-phospholipid-glycolysis metabolism axis can be blocked by specific inhibitors that significantly disrupt the tumor energy metabolism and suppress tumor proliferation and , suggesting that targeting ATP synthesis inhibition in cancer cells might be an attractive therapeutic avenue in GBM management.

The large-scale genomic analysis classifies glioblastoma (GBM) into three major subtypes, including classical (CL), proneural (PN), and mesenchymal (MES) subtypes. Each of these subtypes exhibits a varying degree of sensitivity to the temozolomide (TMZ) treatment, while the prognosis corresponds to the molecular and genetic characteristics of the tumor cell type. Tumors with MES features are predominantly characterized by the NF1 deletion/alteration, leading to sustained activation of the RAS and PI3K-AKT signaling pathways in GBM and tend to acquire drug resistance, resulting in the worst prognosis compared to other subtypes (PN and CL). Here, we used the CRISPR/Cas9 library screening technique to detect TMZ-related gene targets that might play roles in acquiring drug resistance, using overexpressed KRAS-G12C mutant GBM cell lines. The study identified a key therapeutic strategy to address the chemoresistance against the MES subtype of GBM. The CRISPR-Cas9 library screening was used to discover genes associated with TMZ resistance in the U87-KRAS (U87-MG which is overexpressed KRAS-G12C mutant) cells. The patient-derived GBM primary cell line TBD0220 was used for experimental validations in vivo and in vitro. Chromatin isolation by RNA purification (ChIRP) and chromatin immunoprecipitation (ChIP) assays were used to elucidate the silencing mechanism of tumor suppressor genes in the MES-GBM subtype. The small-molecule inhibitor EPIC-0412 was obtained through high-throughput screening. Transmission electron microscopy (TEM) was used to characterize the exosomes (Exos) secreted by GBM cells after TMZ treatment. Blood-derived Exos-based targeted delivery of siRNA, TMZ, and EPIC-0412 was optimized to tailor personalized therapy in vivo. Using the genome-wide CRISPR-Cas9 library screening, we found that the ERBIN gene could be epigenetically regulated in the U87-KRAS cells. ERBIN overexpression inhibited the RAS signaling and downstream proliferation and invasion effects of GBM tumor cells. EPIC-0412 treatment inhibited tumor proliferation and EMT progression by upregulating the ERBIN expression both in vitro and in vivo. Genome-wide CRISPR-Cas9 screening also identified RASGRP1(Ras guanine nucleotide-releasing protein 1) and VPS28(Vacuolar protein sorting-associated protein 28) genes as synthetically lethal in response to TMZ treatment in the U87-KRAS cells. We found that RASGRP1 activated the RAS-mediated DDR pathway by promoting the RAS-GTP transformation. VPS28 promoted the Exos secretion and decreased intracellular TMZ concentration in GBM cells. The targeted Exos delivery system encapsulating drugs and siRNAs together showed a powerful therapeutic effect against GBM in vivo. We demonstrate a new mechanism by which ERBIN is epigenetically silenced by the RAS signaling in the MES subtype of GBM. Restoration of the ERBIN expression with EPIC-0412 significantly inhibits the RAS signaling downstream. RASGRP1 and VPS28 genes are associated with the promotion of TMZ resistance through RAS-GDP to RAS-GTP transformation and TMZ efflux, as well. A quadruple combination therapy based on a targeted Exos delivery system demonstrated significantly reduced tumor burden in vivo. Therefore, our study provides new insights and therapeutic approaches for regulating tumor progression and TMZ resistance in the MES-GBM subtype.

Tumor Treating Fields (TTFields) in combination with temozolomide (TMZ) provides significant survival benefits in glioblastoma (GBM), but prolonged daily use of TTFields compromises patient compliance and cost-effectiveness. Paclitaxel (PTX) has potential synergistic effects with TTFields, but its efficacy is limited by the blood-brain barrier (BBB). The BBB penetration efficiency of receptor-mediated nanocarriers is limited by low endocytosis activity and lysosomal entrapment in brain endothelial cells. To overcome this limitation, we developed lysophosphatidylcholine (LPC)-engineered liposomes (LPC-Lipo) to activate brain endothelial transcytosis for BBB crossing PTX delivery and established a paclitaxel liposomes-electric fields-TMZ (TALECT) regimen for TTFields-based GBM therapy. The transcytosis behavior and mechanism of LPC-Lipo were investigated in both and BBB models. PTX delivery efficiency of LPC-Lipo and the therapeutic efficacy of TALECT regimen were evaluated in a GBM patient-derived xenograft model. Leveraging our findings that LPC can activate brain endothelial transcytosis, LPC-Lipo was developed and exhibited enhanced transcytosis efficiency through accelerated endocytosis and directional trafficking to recycling endosomes (bypassing lysosomes) mediated by p62/SQSTM1, thereby achieving efficient BBB penetration. PTX-loaded LPC-Lipo achieved effective GBM suppression, and this efficacy was replicated in the clinical-grade Lipusu upon LPC engineering. Integrating optimized PTX delivery with the TTFields/TMZ combination established the TALECT regimen. TALECT therapy achieved potent therapy outcomes while reducing daily TTFields exposure by 75%. This efficacy stems from PTX's dual sensitization: (1) to TTFields via microtubule disruption-induced mitotic arrest, and (2) to TMZ by inhibiting DNA damage repair. This work presents a novel transcytosis-activating platform for BBB penetration and proposes the clinically translatable TALECT regimen, advancing the cost-effectiveness of TTFields-based GBM therapy.

Aims To investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair‐related genes and the development of chemoresistance in gliomas. Methods We conducted a comprehensive analysis of deep‐targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I‐TASSER for homology modeling. We elucidated the functional changes induced by high‐frequency site mutations in these genes and investigated their impact on glioma progression. Results The analysis of sequencing mutation results of deep targeted genes in integration revealed that ARID1A gene mutation occurs frequently in glioblastoma and alteration of ARID1A could affect the tolerance of glioma cells to temozolomide treatment. The deletion of proline at position 16 in the ARID1A protein affected the stability of binding of the SWI/SNF core subunit BRG1, which in turn affected the stability of the SWI/SNF complex and led to altered histone modifications in the CDKN1A promoter region, thereby affecting the biological activity of glioma cells, as inferred from modeling and protein interaction analysis. Conclusion The ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance. Deep sequencing targeting DNA damage repair pathways identifies ARID1A as a prognostic biomarker for gliomas and its mutation alters SWI/SNF stability increasing the malignant phenotype of GBM and mediating chemoresistance.

Glioma stem cells (GSCs) play a critical role in the poor treatment outcomes observed in glioblastoma (GBM) patients. A primary focus of current glioma research is understanding the maintenance of stemness in GSCs and their interactions with the tumor microenvironment. In GBMs, the perivascular niche serves as a protective environment for GSCs, contributing to tumor recurrence. However, the molecular mechanisms that sustain this reservoir remain poorly understood. The analysis of single-cell transcriptional data in GBM was conducted to identify signaling pathways in endothelial cells (ECs) that promote stemness traits in glioma cells. Histological staining and the IvyGAP dataset were utilized to evaluate the anatomical microenvironment of glioma. The molecular mechanisms underlying the maintenance of stemness in GSCs, influenced by ECs, were assessed using ELISA, Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), in vivo ubiquitination assays, and other molecular biology experiments. An orthotopic xenograft model was employed to examine the stemness phenotype of GBM cells in the presence of ECs, as well as the synergistic effects of GSK690693 and AMD3100 in inhibiting GBM cells. We found that GSCs are located in close proximity to microvessels, and we identified the CXCL12-CXCR4 signaling pathway in ECs as a promoter of stemness traits in glioma cells. GBM cells can transition to a stem-like state in response to stromal cell-derived factor-1α (SDF-1α) secreted by ECs. This transition activates the CXCR4-mediated AKT/NF-κB signaling pathway, leading to the subsequent upregulation of glioma-associated oncogene homolog 1 (GLI1), a key transcription factor for maintaining stemness. Furthermore, we discovered that SDF-1α influences the turnover of GLI1 protein in GBM cells by modulating GLI1-associated polyubiquitin chains through the phosphorylation of the deubiquitinase USP28 at serine 67. This modification enhances the stemness-maintaining properties of GLI1 via both transcriptional regulation and protein quality control mechanisms. Preclinical studies indicated that the combination of the CXCR4 antagonist AMD3100 and the AKT inhibitor GSK690693 synergistically inhibits GBM cell progression. Our findings unveil a novel signaling axis between ECs and tumor cells that directly impacts the acquisition of stemness traits, suggesting that targeting this pathway could represent a promising therapeutic strategy against GBM.

The rational design and precise synthesis of multifunctional hybrid nanostructures with a tailored active core and a large, dendritic, modified mesoporous structured shell can promote catalysis, energy storage, and biological applications. Here, an oil-water biphase stratification coating strategy has been developed to prepare monodisperse magnetic dendritic mesoporous silica core-shell structured nano- spheres. These sophisticated Fe3O4@SiO2@dendritic-mSiO2 nanospheres feature large dendritic open pores （2.7 and 10.3 nm）. Significantly, the silica shells can be converted into dendritic mesoporous aluminosilicate frameworks with unchanged porosity, a Si/Al molar ratio of 14, and remarkably strong acidic sites, through a post-synthesis approach. In addition, the resultant magnetic dendritic mesoporous aluminosilicate nanospheres exhibit outstanding properties and promising application in phosphate removal from wastewater.

Considering the extensive functional redundancy in microbial communities and great difficulty in elucidating it based on taxonomic structure, studies on the biogeography of soil microbial activity at large spatial scale are as important as microbial community structure. Eighty-four soil samples were collected across a region from south to north China (about 1,000 km) to address the questions if microbial activity displays biogeographic patterns and what are driving forces. These samples represented different soil types, land use and climate. Redundancy analysis and nonmetric multidimensional scaling clearly revealed that soil microbial activities showed distinct differentiation at different sites over a regional spatial scale, which were strongly affected by soil pH, total P, rainfall, temperature, soil type and location. In addition, microbial community structure was greatly influenced by rainfall, location, temperature, soil pH and soil type and was correlated with microbial activity to some extent. Our results suggest that microbial activities display a clear geographic pattern that is greatly altered by geographic distance and reflected by climate, soil pH and total P over large spatial scales. There are common (distance, climate, pH and soil type) but differentiated aspects (TP, SOC and N) in the biogeography of soil microbial community structure and activity.