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Change detection (CD) from multitemporal remote sensing (RS) images plays a crucial role in various fields. Motivated by the advancements in deep learning within computer vision, numerous deep learning-based methodologies have been proposed for CD. However, the intricate backgrounds inherent in RS images present challenges to CD algorithms, leaving a notable disparity from practical applications. The changed regions between RS images frequently related to salient targets, yet encoding modules tend to forfeit the spatial information of these targets and disregard their spatial correlations during feature interaction. Consequently, leveraging the spatial correlation among targets emerges as a pivotal concern for CD algorithms. In this article, a multistage spatial attention network with mixed feature interaction (MAMI-CD) is proposed, which introduces two novel modules, i.e., a multistage attention module (MAM) and a mixed feature interaction module (MIM). The MAM extracts spatial attention features from encoding stages and transfers them to the decoding stages, thereby preserving the spatial information of targets while mitigating the influence of background noise. The MIM employs a channel-wise feature interaction instead of the traditional direct concatenation operation, enhancing the correlations between targets. MAMI-CD has been experimentally evaluated on three public datasets. On the LEVIR-CD, S2Looking, and CDD datasets, our method outperformed the state-of-the-art by 0.65%, 0.93%, and 3.16% F1 score, respectively, thus affirming the beneficial impacts of spatial correlations in CD tasks.

Abstract Background Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. Conclusions DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Abstract Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late‐stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour‐host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR‐146a‐5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR‐146a‐5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour‐promoting cytokines (IL‐6, IL‐8, MCP‐1 and CXCL1). Brain metastases were significantly reduced following miR‐146a‐5p knockdown. Corroborating these findings, miR‐146a‐5p inhibition led to a reduction of IL‐6, IL‐8, MCP‐1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR‐146a‐5p inhibitor, both in vitro and in vivo. Our results highlight the pro‐metastatic function of miR‐146a‐5p in EVs and identifies deserpidine for targeted adjuvant treatment.

Abstract Background The tripartite motif (TRIM) family of proteins plays a key role in the developmental growth and therapeutic resistance of many tumors. However, the regulatory mechanisms and biological functions of TRIM proteins in human glioblastoma (GBM) are not yet fully understood. In this study, we focused on TRIM56, which emerged as the most differentially expressed TRIM family member with increased expression in GBM. Methods Western blot, real-time quantitative PCR (qRT-PCR), immunofluorescence (IF) and immunohistochemistry (IHC) were used to study the expression levels of TRIM56 and cIAP1 in GBM cell lines. Co-immunoprecipitation (co-IP) was used to explore the specific binding between target proteins and TRIM56. A xenograft animal model was used to verify the tumor promoting effect of TRIM56 on glioma in vivo. Results We observed elevated expression of TRIM56 in malignant gliomas and revealed that TRIM56 promoted glioma progression in vitro and in a GBM xenograft model in nude mice. Analysis of the Human Ubiquitin Array and co-IPs showed that cIAP1 is a protein downstream of TRIM56. TRIM56 deubiquitinated cIAP1, mainly through the zinc finger domain (amino acids 21–205) of TRIM56, thereby reducing the degradation of cIAP1 and thus increasing its expression. TRIM56 also showed prognostic significance in overall survival of glioma patients. Conclusions TRIM56-regulated post-translational modifications may contribute to glioma development through stabilization of cIAP1. Furthermore, TRIM56 may serve as a novel prognostic indicator and therapeutic molecular target for GBM.

Abstract Background Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear. Methods Thirteen non-m6A-related neoantigen-coding lncRNAs were selected for analysis from the TransLnc database. Next, a neoantigen activation score (NAS) model was established based on the characteristics of the lncRNAs. Machine learning was employed to expand the model to two additional RNA-seq and two single-cell sequencing datasets for further validation. The DLpTCR algorithm was used to predict T cell receptor (TCR)-peptide binding probability. Results The non-m6A-related NAS model predicted patients’ overall survival outcomes more precisely than the m6A-related NAS model. Furthermore, the non-m6A-related NAS was positively correlated with tumor cells’ evolutionary level, immune infiltration, and antigen presentation. However, high NAS gliomas also showed more PD-L1 expression and high mutation frequencies of T-cell positive regulators. Interestingly, results of intercellular communication analysis suggest that T cell-high neoplastic cell interaction is weaker in both of the NAS groups which might arise from decreased IFNGR1 expression. Moreover, we identified unique TCR-peptide pairs present in all glioma samples based on peptides encoded by the 13 selected lncRNAs. And increased levels of neoantigen-active TCR patterns were found in high NAS gliomas. Conclusions Our work suggests that non-m6A-related neoantigen-coding lncRNAs play an essential role in glioma progression and that screened TCR clonotypes might provide potential avenues for chimeric antigen receptor T cell (CAR-T) therapy for gliomas.

A scheme for optical nonreciprocity is proposed via dual-mode Raman process in thermal atoms. We investigate a far-detuned nonlinear Raman process, with the assistance of the Doppler effect to achieve chiral optical nonlinearity. The resulting Kerr nonlinear absorption is subject to a direction-dependent Doppler shifts seen by the thermal atoms. Moreover, the inter-channel Raman interference could significantly enhance Kerr nonlinear absorption for probe field, leading to the enhancement of the optical nonreciprocity. Simulation results show that the isolation ratio could reach 41 dB and the insertion loss is about 0.16 dB, with bandwidth up to 2π ×48 MHz. Furthermore, the sensitivity of the system is investigated under different strengths of the control and Raman fields.

Abstract Glioblastoma (GBM) is the most aggressive brain tumor of the central nervous system. Recent studies have reported the crucial functions of Tripartite Motif Containing 24 (TRIM24) in promoting cancer progression of GBM. However, it remains unclear if TRIM24 is an attractive druggable target for therapeutic intervention in GBM. We therefore performed a series of experiments, aiming to verify whether specific TRIM24 inhibition suppresses GBM malignant functions using dTRIM24 and IACS-9571, two novel selective TRIM24 antagonists. Our data showed that TRIM24 inhibitors serve as effective agents for inhibiting cell propagation and invasion of several patient-derived GBM stem cells (GSCs), and these effects are mediated partially through suppression of the TRIM24-SOX2 axis. This study provides novel insight into the TRIM24-based druggable dependencies, important for developing effective therapeutic strategies for brain tumors.

Glioblastoma multiforme (GBM) is a common central neural system malignant tumor among adults. Alongside its microscopic spread, immunosuppression in the tumor microenvironment also induces its refractoriness, which makes immunotherapy for GBM particularly important. Unfortunately, traditional immune checkpoint inhibitors (ICIs) often show limited therapeutic effects in GBM clinical trials, and new therapeutic strategies or targets are urgently needed. TNFSF14/LIGHT is a novel immune checkpoint molecule that plays essential roles in both innate and acquired immunity. Despite recent advances in our understanding of the function of TNFSF14/LIGHT in a variety of cancer types, the clinical and immunological importance of TNFSF14/LIGHT in human gliomas has not been fully explained. Here, we employed a comprehensive in silico analysis with publicly available data to analyze the molecular and immune characteristics of TNFSF14/LIGHT to explore its feasibility as an immunotherapy target. Totally, 2215 glioma cases were enrolled in the current study. Immunohistochemistry staining based on patient tissues (n = 34) was performed for the validation. TNFSF14/LIGHT was expressed higher in higher-WHO-grade gliomas and mesenchymal subtypes, and it was sensitive as a prognostic marker in GBM and low-grade glioma (LGG). A nomogram prognostic model was established based on TNFSF14/LIGHT expression together with other risk factors. Additionally, Gene Ontology and pathway analysis revealed that TNFSF14/LIGHT participated in T-cell activities and inflammatory processes. Moreover, analysis based on the structure and interactions of TNFSF14/LIGHT revealed its mutation sites in tumors as well as crucial interacting proteins. Analysis of IMvigor210 indicated the role of TNFSF14/LIGHT in immunotherapy. Altogether, our results reveal an underlying role of TNFSF14/LIGHT as an immunotherapy target in GBM.

The expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) can lead to tumor cell resistance to alkylating agents. Glioblastomas with isocitrate dehydrogenase mutation (IDHmut) were reported to have significantly higher MGMT promoter methylation, which predicted improved outcomes after temozolomide treatment. However, the MGMT methylation status in IDHmut glioma remains controversial. To further explore the associations of MGMT promoter methylation status with other molecular features in IDHmut gliomas, in this work, we analyzed the relationship of MGMT promoter methylation status with 1p/19q codeletion status and age in IDHmut gliomas based on a large Asian (Chinese) cohort. We found that there was no significant difference in MGMT methylation status in IDHmut 1p/19q-codeleted oligodendrogliomas compared to IDHmut astrocytomas, in either primary or recurrent cases. Moreover, the MGMT methylation status was not associated with age. The difference compared to previous research which indicated the MGMT methylation status differed significantly among IDHmut glioma might be caused by differences between populations, indicating that routine assessment of MGMT methylation status in oligodendrogliomas may still be necessary.

Glioma is the most common primary malignant tumor in the central nervous system, and directly affects the quality of life and cognitive function of patients. Ferroptosis, is a new form of regulated cell death characterized by iron-dependent lipid peroxidation. Ferroptosis is mainly due to redox imbalance and involves multiple intracellular biology processes, such as iron metabolism, lipid metabolism, and antioxidants synthesis. Induction of ferroptosis could be a new target for glioma treatment, and ferroptosis-related processes are associated with chemoresistance and radioresistance in glioma. In the present review, we provide the characteristics, key regulators and pathways of ferroptosis and the crosstalk between ferroptosis and other programmed cell death in glioma, we also proposed the application and prospect of ferroptosis in the treatment of glioma.

High-grade glioma is characterized by cell heterogeneity, gene mutations, and poor prognosis. Abnormal copper homeostasis affects the pathogenesis of glioma, but the underlying mechanisms and involved proteins are unknown. Here, we selected 90 copper-related proteins and verified their expression differences in glioma and normal tissues in the TCGA cohort followed by GO and KEGG clustering analyses. We then developed and validated a prognostic model. Moreover, we examined the mutation burden of copper-related proteins and discussed the differences in the immune microenvironment in the high- and low-risk groups. Furthermore, we focused on STEAP2 and demonstrated that STEAP2 expression was relatively low in tumor tissues compared to normal tissues, implying a favorable prognosis. Our findings provide a foundation for future research targeting copper-related proteins and their immune microenvironment to improve prognosis and responses to immunotherapy.

A scheme of optical four-level pulse amplitude modulation (PAM-4) is proposed based on phase-dependent electromagnetic-induced transparency (EIT) in nitrogen-vacancy (NV) centers. For a closed structure, its transmission depends on the relative phase of applied fields. Based on EIT, the PAM-4 may be achieved by encoding the relative phase and decoding the amplitude of the transmission field. Simulation results show that the differential nonlinearity and the integral nonlinearity of the proposed scheme could be reduced by two orders of magnitude compared with that based on Mach–Zehnder modulator scheme, and the ratio of level separation mismatch is closer to the ideal value 1. Furthermore, the improvement of the system at different probe field detunings and coupling field strengths is investigated.

Abstract Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24‐hydroxylase (CYP46A1), a brain‐specific enzyme responsible for the elimination of cholesterol through the conversion of cholesterol into 24(S)‐hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared with normal brain tissue. A reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis in human gliomas. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. RNA‐seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz, an activator of CYP46A1 that is known to penetrate the blood–brain barrier, inhibited GBM growth in vivo. Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.

Recent evidence suggests that dysregulation of iron regulatory factors may play essential roles in cancer pathophysiology. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a metalloreductase, which is vital for cellular iron uptake and homeostasis. However, the clinical significance and function of STEAP3 in the development of human gliomas remain unclear. Through analysis of publicly available databases, we found that STEAP3 was highly expressed in malignant gliomas, especially in the mesenchymal glioma molecular subtype and isocitrate dehydrogenase 1/2 (IDH1/2) wild-type gliomas. Expression levels of STEAP3 in gliomas correlated inversely with patient overall survival (OS) and served as an independent prognostic marker by multivariate Cox regression analysis. In functional assays performed with RNA knockdown, loss of STEAP3 attenuated aggressive phenotypes in glioma cells, including cell proliferation, invasion, and sphere formation in vitro and tumor growth in vivo. Finally, STEAP3 drives these activities by inducing mesenchymal transition, promoting transferrin receptor (TfR) expression, and activating STAT3-FoxM1 axis signaling. Taken together, these results indicate that STEAP3 functions as an oncogenic mediator in glioma progression and is thus a potential therapeutic target for the treatment of the disease.

Abstract Background Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Ironically, studies have recently revealed that radiation can augment malignant progression, by promoting migration and invasion, which make the disease especially difficult to cure. Here, we investigated the anticancer effects of YM155, a purported radiosensitizer, in GBM cell lines. Methods GBM cell lines U251 and U87 were treated with YM155 to assess cytotoxicity and activity of the molecule in vitro. Nude mice were implanted with cells to generate orthotopic xenografts for in vivo studies. Response of cells to treatment was examined using cell viability, immunofluorescence, wound healing, and the Transwell invasion assay. Molecules potentially mediating response were examined through western blot analysis, phospho-kinase arrays, and qPCR. Cells were transfected with siRNA knockdown and gene expression constructs to identify molecular mediators of response. Results YM155 reduced viability of U251 and U87 cells and enhanced radiosensitivity through inhibition of homologous recombination. Besides, YM155 decreased invasion caused by radiation and led to expression changes in molecular markers associated with EMT. STAT3 was one of 10 molecules identified on a phosphokinase array exhibiting significant change in phosphorylation under YM155 treatment. Transfection with STAT3 siRNAs or expression constructs demonstrated that EMT changes were achieved by inhibiting the phosphorylation of STAT3 and were survivin-independent. Finally, combining YM155 and radiation in orthotopic xenografts reduced growth and prolonged overall survival of animals. Conclusions YM155 decreased radiation-induced invasion in GBM cell lines in vitro and in vivo through inhibition of STAT3.

Abstract Background Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Here, we examined the role of GOLM1 in the development of human glioma. Methods qRT-PCR, immunohistochemistry, and western blot analysis were performed to evaluate GOLM1 levels in cell lines and a cohort of primary human glioma and non-neoplastic brain tissue samples. Glioma cell lines were modified with lentiviral constructs expressing short hairpin RNAs targeting GOLM1 or overexpressing the protein to assess function in proliferation, viability, and migration and invasion in vitro using EdU, CCK8, clone-forming, Transwell assays, 3D tumor spheroid invasion assay and in vivo in orthotopic implantations. Protein lysates were used to screen a membrane-based antibody array to identify kinases mediated by GOLM1. Specific inhibitors of PDGFRα (AG1296) and AKT (MK-2206) were used to examine the regulation of PDGFA/PDGFRα on GOLM1 and the underlying pathway respectively. Results qRT-PCR, immunohistochemistry and western blot analysis revealed GOLM1 expression to be elevated in glioma tissues and cell lines. Silencing of GOLM1 attenuated proliferation, migration, and invasion of U251, A172 and P3#GBM (primary glioma) cells, while overexpression of GOLM1 enhanced malignant behavior of U87MG cells. We further demonstrated that activation of AKT is the driving force of GOLM1-promoted glioma progression. The last finding of this research belongs to the regulation of PDGFA/PDGFRα on GOLM1, while GOLM1 was also a key element of PDGFA/PDGFRα-mediated activation of AKT, as well as the progression of glioma cells. Conclusions PDGFA/PDGFRα-regulated GOLM1 promotes glioma progression possibly through activation of a key signaling kinase, AKT. GOLM1 interference may therefore provide a novel therapeutic target and improve the efficacy of glioma treatment, particularly in the case of the proneural molecular subtype of human glioma.

Abstract Background Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo. Methods U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. Results IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 μM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models. Conclusions This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients.

Abstract Background The coiled-coil domain is a structural motif found in proteins that participate in a variety of biological processes. Aberrant expression of such proteins has been shown to be associated with the malignant behavior of human cancers. In this study, we investigated the role of a specific family member, coiled-coil domain containing 109B (CCDC109B), in human gliomas. Methods and results We confirmed that CCDC109B was highly expressed in high grade gliomas (HGG; WHO III–IV) using immunofluorescence, western blot analysis, immunohistochemistry (IHC) and open databases. Through Cox regression analysis of The Cancer Genome Atlas (TCGA) database, we found that the expression levels of CCDC109B were inversely correlated with patient overall survival and it could serve as a prognostic marker. Then, a serious of cell functional assays were performed in human glioma cell lines, U87MG and U251, which indicated that silencing of CCDC109B attenuated glioma proliferation and migration/invasion both in vitro and in vivo. Notably, IHC staining in primary glioma samples interestingly revealed localization of elevated CCDC109B expression in necrotic areas which are typically hypoxic. Moreover, small interfering RNA (siRNA) and specific inhibiters of HIF1α led to decreased expression of CCDC109B in vitro and in vivo. Transwell assay further showed that CCDC109B is a critical factor in mediating HIF1α-induced glioma cell migration and invasion. Conclusion Our study elucidated a role for CCDC109B as an oncogene and a prognostic marker in human gliomas. CCDC109B may provide a novel therapeutic target for the treatment of human glioma.

Galangin (GG), a flavonoid, elicits a potent antitumor activity in diverse cancers. Here, we evaluated the efficacy of GG in the treatment of human glioblastoma multiforme (GBM) and investigated the molecular basis for its inhibitory effects in the disease. GG inhibited viability and proliferation of GBM cells (U251, U87MG, and A172) in a dose-dependent manner (IC50 = 221.8, 262.5, 273.9 μM, respectively; P < 0.001; EdU, ~40% decrease at 150 μM, P < 0.001), and the number of colonies formed was significantly reduced (at 50 μM, P < 0.001). However, normal human astrocytes were more resistant to its cytotoxic effects (IC50 >450 μM). Annexin-V/PI staining was increased indicating that GG induced apoptosis in GBM cells (26.67 and 30.42%, U87MG and U251, respectively) and associated proteins including BAX and cleaved PARP-1 were increased (~3×). Cells also underwent pyroptosis as determined under phase-contrast microscopy. Knockdown of gasdermin E (GSDME), a protein involved in pyroptosis, alleviated pyroptosis induced by GG through aggravating nuclear DNA damage in GBM cells. Meanwhile, fluorescent GFP-RFP-MAP1LC3B puncta associated with autophagy increased under GG treatment, and transmission electron microscopy confirmed the formation of autophagic vesicles. Inhibition of autophagy enhanced GG-induced apoptosis and pyroptosis in GBM cells. Finally, in an orthotopic xenograft model in nude mice derived from U87MG cells, treatment with GG in combination with an inhibitor of autophagy, chloroquine, suppressed tumor growth, and enhanced survival compared to GG monotherapy (P < 0.05). Our results demonstrated that GG simultaneously induces apoptosis, pytoptosis, and protective autophagy in GBM cells, indicating that combination treatment of GG with autophagy inhibitors may be an effective therapeutic strategy for GBM.