RESUMEN
Filter pruning has gained widespread adoption for the purpose of compressing and speeding up convolutional neural networks (CNNs). However, the existing approaches are still far from practical applications due to biased filter selection and heavy computation cost. This article introduces a new filter pruning method that selects filters in an interpretable, multiperspective, and lightweight manner. Specifically, we evaluate the contributions of filters from both individual and overall perspectives. For the amount of information contained in each filter, a new metric called information capacity is proposed. Inspired by the information theory, we utilize the interpretable entropy to measure the information capacity and develop a feature-guided approximation process. For correlations among filters, another metric called information independence is designed. Since the aforementioned metrics are evaluated in a simple but effective way, we can identify and prune the least important filters with less computation cost. We conduct comprehensive experiments on benchmark datasets employing various widely used CNN architectures to evaluate the performance of our method. For instance, on ILSVRC-2012, our method outperforms state-of-the-art methods by reducing floating-point operations (FLOPs) by 77.4% and parameters by 69.3% for ResNet-50 with only a minor decrease in an accuracy of 2.64%.
RESUMEN
BACKGROUND: Immunotherapy has emerged as a novel strategy for cancer treatment following surgery, radiotherapy, and chemotherapy. Immune checkpoint blockade and Chimeric antigen receptor (CAR)-T cell therapies have been successful in clinical trials. Cancer cells evade immune surveillance by hijacking inhibitory pathways via overexpression of checkpoint genes. The Cluster of Differentiation 47 (CD47) has emerged as a crucial checkpoint for cancer immunotherapy by working as a "don't eat me" signal and suppressing innate immune signaling. Furthermore, CD47 is highly expressed in many cancer types to protect cancer cells from phagocytosis via binding to SIRPα on phagocytes. Targeting CD47 by either interrupting the CD47-SIRPα axis or combing with other therapies has been demonstrated as an encouraging therapeutic strategy in cancer immunotherapy. Antibodies and small molecules that target CD47 have been explored in pre- and clinical trials. However, formidable challenges such as the anemia and palate aggregation cannot be avoided because of the wide presentation of CD47 on erythrocytes. AIM OF VIEW: This review summarizes the current knowledge on the regulation and function of CD47, and provides a new perspective for immunotherapy targeting CD47. It also highlights the clinical progress of targeting CD47 and discusses challenges and potential strategies. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review provides a comprehensive understanding of targeting CD47 in cancer immunotherapy, it also augments the concept of combination immunotherapy strategies by employing both innate and adaptive immune responses.
Asunto(s)
Antígeno CD47 , Inmunoterapia , Neoplasias , Antígeno CD47/metabolismo , Antígeno CD47/inmunología , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Animales , Transducción de Señal , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/metabolismo , Inmunidad Innata , FagocitosisRESUMEN
The inherent hydrophilicity and biocompatibility of cotton fabrics facilitated bacterial proliferation and safety concerns, limiting their applications. To address these issues, tyrosine-derived polyetherimide, bis(3-aminopropyl)-terminated poly(dimethylsiloxane), and paraformaldehyde were used to synthesize hyperbranched benzoxazine THB-BOZs-PDMS with potent antibacterial and antibiofilm activity. The protonated amino groups of benzoxazine facilitated electrostatic interactions with negatively charged bacteria, and hydrophobic interactions disrupted the cell membrane, leading to bacteria death. Notably, phytic acid interacts with benzoxazines through intermolecular forces, with its phosphoric acid groups facilitating the curing of benzoxazines, thereby imparting flame-retardant properties to the material. Consequently, a multifunctional coating was developed via LBL self-assembly and in-situ curing of benzoxazines and phytic acid on the fabric surfaces. The successful deposition of the coating was confirmed through compositional analysis and morphological characterization. After 4â¯cycles of LBL modification, the fabrics TBPâ¯+â¯PA-CF-4 displayed outstanding antibacterial efficacy, bacterial anti-adhesion properties, and heat resistance. Furthermore, TBPâ¯+â¯PA-CF-4 exhibited notable washing and mechanical durability, attributed to the stability conferred by in-situ cured of layers. Compared with other reported modified fabrics, TBPâ¯+â¯PA-CF-4 displayed more comprehensive overall performances. These multifunctional fabrics provided a sustainable approach for advancing personal protective materials and public decoration, particularly suited for use in high-humidity environments or military settings.
RESUMEN
Functionalization of Si-bound methyl group provides an efficient access to diverse organosilanes. However, the asymmetric construction of silicon-stereogenic architectures by functionalization of Si-bound methyl group has not yet been described despite recent significant progress in producing chiral silicon. Herein, we disclosed the enantioselective silylmethyl functionalization involving the aryl to alkyl 1,5-palladium migration to access diverse naphthalenes possessing an enantioenriched stereogenic silicon center, which are inaccessible before. It is worthy to note that the realization of asymmetric induction at the step of metal migration itself remains challenging. Our study constitutes the first enantioselective aryl to alkyl 1,5-palladium migration reaction. The key to the success is the discovery and fine-tuning of the different substituents of α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based phosphoramidites, which ensure the enantioselectivity and desired reactivity.
RESUMEN
BACKGROUND: Apoptosis and oxidative stress in kidneys are critical players in acute kidney injury (AKI). Rehmapicrogenin, a monomeric compound extracted from Rehmanniae radix, has been found to possess nitric oxide inhibitory and anti-inflammatory activities. Thus, this study aimed to investigate the roles and mechanisms of rehmapicrogenin in AKI. METHODS: Lipopolysaccharide (LPS) was used to induce AKI-like conditions. Cell survival conditions were detected by cell counting kit-8 assays and flow cytometry. Several renal function markers including blood urea nitrogen, proteinuria, creatinine, and albumin were measured. Apoptosis and reactive oxygen species (ROS) production were examined by TUNEL and dihydroethidium staining, respectively. Haematoxylin-eosin staining and periodic acid-Schiff staining were conducted to assess histopathological changes. Gene expression was evaluated by western blotting, commercially available kits and immunofluorescence staining. RESULTS: For in vitro analysis, rehmapicrogenin inhibited the LPS-induced podocyte apoptosis by activating the Nrf2/ARE pathway. For in vivo analysis, rehmapicrogenin improved renal functions in LPS-induced mice. Additionally, rehmapicrogenin suppressed LPS-induced podocyte apoptosis and oxidative stress in kidney tissues. Mechanistically, rehmapicrogenin activated the Nrf2/ARE pathway in LPS-induced mice. CONCLUSION: Rehmapicrogenin relieves the podocyte injury and renal dysfunctions through activating the Nrf2/ARE pathway to inhibit apoptosis and oxidative stress.
Asunto(s)
Lesión Renal Aguda , Apoptosis , Modelos Animales de Enfermedad , Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Podocitos , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratones , Elementos de Respuesta Antioxidante/efectos de los fármacos , Masculino , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Antioxidantes/farmacologíaRESUMEN
Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.
Asunto(s)
Adenosina Trifosfato , Mitocondrias , Poro de Transición de la Permeabilidad Mitocondrial , Animales , Adenosina Trifosfato/metabolismo , Ratones , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Mitocondrias/metabolismo , Humanos , Forma Mitocondrial de la Creatina-Quinasa/metabolismo , Forma Mitocondrial de la Creatina-Quinasa/genética , Transducción de Señal/fisiología , Modelos Animales de EnfermedadRESUMEN
[This retracts the article DOI: 10.3892/etm.2021.9949.].
RESUMEN
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.
Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , Epigénesis Genética , Neoplasias Pancreáticas , Microambiente Tumoral , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Ratones , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismoRESUMEN
Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with a risk associated with hormonal and reproductive factors. However, the potential causal effects between these factors and SLE remain unclear. A two-sample Mendelian randomization study was conducted using the published summary data from the genome-wide association study database. Five independent genetic variants associated with hormonal and reproductive factors were selected as instrumental variables: age at menarche, age at natural menopause, estradiol, testosterone, and follistatin. To estimate the causal relationship between these exposure factors and disease outcome, we employed the inverse-variance weighted, weighted median, and MR-Egger methods. In addition, we carried out multiple sensitivity analyses to validate model assumptions. Inverse variance weighted showed that there was a causal association between circulating follistatin and SLE risk (OR = 1.38, 95% CI 1.03 to 1.86, P = 0.033). However, no evidence was found that correlation between AAM (OR = 1.04, 95% CI 0.77 to 1.40, P = 0.798), ANM (OR = 0.99, 95% CI 0.92 to 1.06, P = 0.721), E2 (OR = 1.40, 95% CI 0.14 to 13.56, P = 0.772), T (OR = 1.25, 95% CI 0.70 to 2.28, P = 0.459), and SLE risk. Our study revealed that elevated circulating follistatin associates with an increased risk of SLE. This finding suggests that the regulatory signals mediated by circulating follistatin may provide a potential mechanism relevant to the treatment of SLE.
Asunto(s)
Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico , Análisis de la Aleatorización Mendeliana , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/sangre , Femenino , Folistatina/genética , Folistatina/sangre , Menarquia , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Factores de Riesgo , Riesgo , Testosterona/sangre , Reproducción/genética , Menopausia , Estradiol/sangreRESUMEN
Background: Cervical cancer is a significant global health burden, and individualized treatment approaches are necessary due to its heterogeneity. Radiotherapy is a common treatment modality; however, the response varies among patients. The identification of reliable biomarkers to predict radiotherapy sensitivity is crucial. Methods: A cohort of 189 patients with stage IB2-IVA cervical cancer, treated with radiotherapy alone or concurrent chemoradiotherapy, was included. Serum samples were collected before treatment, and intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) concentrations were determined. Patients were categorized into radiotherapy-sensitive (RS) and radiotherapy-resistant (RR) groups based on treatment response. Clinicopathological characteristics and survival rates were analyzed. Results: The analysis of clinicopathological characteristics showed that age, family history of cervical cancer and post-menopausal status did not significantly differ between RS and RR groups. Tumor size demonstrated a borderline significant association with radiotherapy response, while differentiation degree was significantly associated. Serum ICAM-1 and VCAM-1 concentrations were significantly higher in the RR group compared to the RS group. Combined detection of ICAM-1 and VCAM-1 improved the predictive ability for radiotherapy sensitivity. Higher serum ICAM-1 and VCAM-1 levels were observed in patients with lower tumor differentiation. Five-year overall survival rates differed significantly between patients with high and low ICAM-1 and VCAM-1 levels. Conclusion: Serum ICAM-1 and VCAM-1 levels show potential as predictive biomarkers for radiotherapy sensitivity in cervical cancer.
RESUMEN
Roads are the fundamental elements of transportation, connecting cities and rural areas, as well as people's lives and work. They play a significant role in various areas such as map updates, economic development, tourism, and disaster management. The automatic extraction of road features from high-resolution remote sensing images has always been a hot and challenging topic in the field of remote sensing, and deep learning network models are widely used to extract roads from remote sensing images in recent years. In light of this, this paper systematically reviews and summarizes the deep-learning-based techniques for automatic road extraction from high-resolution remote sensing images. It reviews the application of deep learning network models in road extraction tasks and classifies these models into fully supervised learning, semi-supervised learning, and weakly supervised learning based on their use of labels. Finally, a summary and outlook of the current development of deep learning techniques in road extraction are provided.
RESUMEN
Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patología , Neoplasias Encefálicas/patología , Tomografía con Microscopio Electrónico , Encéfalo/patología , Mitocondrias/patologíaRESUMEN
Polyurethane-cement composite are widely used in modern civil engineering, and the method of adding diluent is often used to adjust the construction process to adapt to the engineering environment. Studies have shown that the addition of diluent impacts the performance of polyurethane-cement based composite surface coatings, but there have been few reports on the influence of diluent content on the mechanical properties and microstructure of the coatings. To address this, polyurethane coatings with different diluent contents were prepared, and positron annihilation lifetime spectroscopy was used to test the microstructure of the coatings. The tensile strength and elongation at rupture were tested using a universal material testing machine, and the fracture interface morphology of each coating was observed by scanning electron microscopy. Finally, the correlation between the microstructure parameters and the mechanical properties of the coating was analyzed using grey relation theory. The results demonstrated that with the increase in diluent content, (i) the average radius of the free volume hole (R) and the free volume fraction (FV) of the coating both showed a trend of first decreasing and then increasing. The value of R was between 3.04 and 3.24 Å, and the value of FV was between 2.08 and 2.84%. (ii) The tensile strength of the coating increased first and then decreased, while the elongation at rupture decreased first and then increased. Among them, the value of tensile strength was between 3.23 and 4.02 MPa, and the value of elongation at fracture was between 49.34 and 63.04%. In addition, the free volume in polymers plays a crucial role in facilitating the migration of molecular chain segments and is closely related to the macroscopic mechanical properties of polymers. A correlation analysis showed that the R value of the coating had the greatest influence on its tensile strength, while FV showed a higher correlation with the elongation at rupture.
RESUMEN
To explore the role of forkhead box protein O1 (FOXO1) in the progression of glioblastoma multiforme (GBM) and related drug resistance, we deciphered the roles of FOXO1 and miR-506 in proliferation, apoptosis, migration, invasion, autophagy, and temozolomide (TMZ) sensitivity in the U251 cell line using in vitro and in vivo experiments. Cell viability was tested by a cell counting kit-8 (CCK8) kit; migration and invasion were checked by the scratching assay; apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and flow cytometry. The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506. Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment. We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ, which was mediated by autophagy. FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation. MiR-506 could downregulate E26 transformation-specific 1 (ETS1) expression by targeting its 3'-untranslated region (UTR). Interestingly, ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells. Consistently, both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models. Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity. Thus, the above axis might be a promising therapeutic target for GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , MicroARNs , Animales , Ratones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos , Retroalimentación , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Temozolomida/farmacología , Temozolomida/uso terapéutico , Humanos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismoRESUMEN
PURPOSE: Glioma has been demonstrated as one of the most malignant intracranial tumors and currently there is no effective treatment. Based on our previous RNA-sequencing data for oxidative phosphorylation (OXPHOS)-inhibition resistant and OXPHOS-inhibition sensitive cancer cells, we found that vimentin (VIM) is highly expressed in the OXPHOS-inhibition resistant cancer cells, especially in glioma cancer cells. Further study of VIM in the literature indicates that it plays important roles in cancer progression, immunotherapy suppression, cancer stemness and drug resistance. However, its role in glioma remains elusive. This study aims to decipher the role of VIM in glioma, especially its role in OXPHOS-inhibition sensitivity, which may provide a promising therapeutic target for glioma treatment. METHODS: The expression of VIM in glioma and the normal tissue has been obtained from The Cancer Genome Atlas (TCGA) database, and further validated in Human Protein Atlas (HPA) and Chinese Glioma Genome Atlas (CGGA). And the single-cell sequencing data was obtained from TISCH2. The immune infiltration was calculated via Tumor Immune Estimation Resource (TIMER), Estimation of Stromal and Immune Cells in Malignant Tumors using Expression Data (ESTIMATE) and ssGSEA, and the Immunophenoscore (IPS) was calculated via R package. The differentiated expressed genes were analyzed including GO/KEGG and Gene Set Enrichment Analysis (GSEA) between the VIM-high and -low groups. The methylation of VIM was checked at the EWAS and Methsurv. The correlation between VIM expression and cancer stemness was obtained from SangerBox. We also employed DepMap data and verified the role of VIM by knocking down it in VIM-high glioma cell and over-expressing it in VIM-low glioma cells to check the cell viability. RESULTS: Vim is highly expressed in the glioma patients compared to normal samples and its high expression negatively correlates with patients' survival. The DNA methylation in VIM promoters in glioma patients is lower than that in the normal samples. High VIM expression positively correlates with the immune infiltration and tumor progression. Furthermore, Vim is expressed high in the OXPHOS-inhibition glioma cancer cells and low in the OXPHOS-inhibition sensitive ones and its expression maintains the OXPHOS-inhibition resistance. CONCLUSIONS: In conclusion, we comprehensively deciphered the role of VIM in the progression of glioma and its clinical outcomes. Thus provide new insights into targeting VIM in glioma cancer immunotherapy in combination with the current treatment.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/genética , Metilación de ADN/genética , Glioma/genética , Fosforilación Oxidativa , VimentinaRESUMEN
BACKGROUND: Glioma is a lethal brain cancer and lacking effective therapies. Challenges include no effective therapeutic target, intra- and intertumoral heterogeneity, inadequate effective drugs, and an immunosuppressive microenvironment, etc. Deciphering the pathogenesis of gliomas and finding out the working mechanisms are urgent and necessary for glioma treatment. Identification of prognostic biomarkers and targeting the biomarker genes will be a promising therapy. METHODS: From our RNA-sequencing data of the oxidative phosphorylation (OXPHOS)-inhibition sensitive and OXPHOS-resistant cell lines, we found that the scaffolding protein caveolin 1 (CAV1) is highly expressed in the resistant group but not in the sensitive group. By comprehensive analysis of our RNA sequencing data, Whole Genome Bisulfite Sequencing (WGBS) data and public databases, we found that CAV1 is highly expressed in gliomas and its expression is positively related with pathological processes, higher CAV1 predicts shorter overall survival. RESULTS: Further analysis indicated that (1) the differentiated genes in CAV1-high groups are enriched in immune infiltration and immune response; (2) CAV1 is positively correlated with tumor metastasis markers; (3) the methylation level of CAV1 promoters in glioma group is lower in higher stage than that in lower stage; (4) CAV1 is positively correlated with glioma stemness; (5) higher expression of CAV1 renders the glioma cells' resistant to oxidative phosphorylation inhibitors. CONCLUSION: Therefore, we identified a key gene CAV1 and deciphered its function in glioma progression and prognosis, proposing that CAV1 may be a therapeutic target for gliomas.
RESUMEN
Although Al is not necessary or even toxic to most plants, it is beneficial for the growth of tea plants. However, the mechanism through which Al promotes root growth in tea plants remains unclear. In the present study, we found that flavonol glycoside levels in tea roots increased following Al treatment, and the Al-induced UDP glycosyltransferase CsUGT84J2 was involved in this mechanism. Enzyme activity assays revealed that rCsUGT84J2 exhibited catalytic activity on multiple types of substrates, including phenolic acids, flavonols, and auxins in vitro. Furthermore, metabolic analysis with UPLC-QqQ-MS/MS revealed significantly increased flavonol and auxin glycoside accumulation in CsUGT84J2-overexpressing Arabidopsis thaliana. In addition, the expression of genes involved in the flavonol pathway as well as in the auxin metabolism, transport, and signaling pathways was remarkably enhanced. Additionally, lateral root growth and exogenous Al stress tolerance were significantly improved in transgenic A. thaliana. Moreover, gene expression and metabolic accumulation related to phenolic acids, flavonols, and auxin were upregulated in CsUGT84J2-overexpressing tea plants but downregulated in CsUGT84J2-silenced tea plants. In conclusion, Al treatment induced CsUGT84J2 expression, mediated flavonol and auxin glycosylation, and regulated endogenous auxin homeostasis in tea roots, thereby promoting the growth of tea plants. Our findings lay the foundation for studying the precise mechanisms through which Al promotes the growth of tea plants.
RESUMEN
Background: Glioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. However, the role of QPCTL in glioma and the relationship between its expression and clinical outcomes remains unclear. Deciphering the role of QPCTL in glioma will provide a promising therapy for glioma cancer immunotherapy. Methods: QPCTL expression in glioma tissues and normal adjacent tissues was primarily analyzed in The Cancer Genome Atlas (TCGA) database, and further validated in another independent cohort from the Gene Expression Omnibus (GEO) database, Chinese Glioma Genome Atlas (CGGA), and Human Protein Atlas (HPA). The relationships between QPCTL expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which QPCTL interacted was built using the online STRING website. Meanwhile, we use Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate the relationships between QPCTL expression and infiltrated immune cells and their corresponding gene marker sets. We analyzed the Differentially Expressed Genes (DEGs) including GO/KEGG and Gene Set Enrichment Analysis (GSEA) based on QPCTL-high and -low expression tumors. Results: In contrast to normal tissue, QPCTL expression was higher in glioma tumor tissue (p < 0.05). Higher QPCTL expression was closely associated with high-grade malignancy and advanced tumor stage. Univariate and multivariate analysis indicated the overall survival of glioma patients with higher QPCTL expression is shorter than those with lower QPCTL expression (p < 0.05). Glioma with QPCTL deficiency presented the paucity of infiltrated immune cells and their matching marker sets. Moreover, QPCTL is essential for glioma cell proliferation and tumor growth and is a positive correlation with glioma cell stemness. Conclusion: High QPCTL expression predicts high grades of gliomas and poor prognosis with impaired infiltration of adaptive immune cells in the tumor microenvironment as well as higher cancer stemness. Moreover, targeting QPCTL will be a promising immunotherapy in glioma cancer treatment.
Asunto(s)
Neoplasias Encefálicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Glioma , Humanos , Antígeno CD47 , Glioma/genética , Glioma/terapia , Inmunoterapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Microambiente TumoralRESUMEN
Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells, has revolutionized the oncology landscape as it utilizes patients' own immune systems in combating the cancer cells. Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such as CD47, CD24, MHC-I, PD-L1, STC-1 and GD2, have emerged as essential checkpoints for cancer immunotherapy by functioning as "don't eat me" signals or interacting with "eat me" signals to suppress immune responses. Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy. Genetic ablation of these phagocytosis checkpoints, as well as blockade of their signaling pathways, robustly augments phagocytosis and reduces tumor size. Among all phagocytosis checkpoints, CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment. CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials. However, anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes. Here, we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy, highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.