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BACKGROUND: Molecular classification has laid the framework for exploring glioma biology and treatment strategies. Pro-neural to mesenchymal transition (PMT) of glioma is known to be associated with aggressive phenotypes, unfavorable prognosis, and treatment resistance. Recent studies have highlighted that long non-coding RNAs (lncRNAs) are key mediators in cancer mesenchymal transition. However, the relationship between lncRNAs and PMT in glioma has not been systematically investigated. METHODS: Gene expression profiles from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GSE16011, and Rembrandt with available clinical and genomic information were used for analyses. Bioinformatics methods such as weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis (GSEA), Cox analysis, and least absolute shrinkage and selection operator (LASSO) analysis were performed. RESULTS: According to PMT scores, we confirmed that PMT status was positively associated with risky behaviors and poor prognosis in glioma. The 149 PMT-related lncRNAs were identified by WGCNA analysis, among which 10 (LINC01057, TP73-AS1, AP000695.4, LINC01503, CRNDE, OSMR-AS1, SNHG18, AC145343.2, RP11-25K21.6, RP11-38L15.2) with significant prognostic value were further screened to construct a PMT-related lncRNA risk signature, which could divide cases into two groups with distinct prognoses. Multivariate Cox regression analyses indicated that the signature was an independent prognostic factor for high-grade glioma. High-risk cases were more likely to be classified as the mesenchymal subtype, which confers enhanced immunosuppressive status by recruiting macrophages, neutrophils, and regulatory T cells. Moreover, six lncRNAs of the signature could act as competing endogenous RNAs to promote PMT in glioblastoma. CONCLUSIONS: We profiled PMT status in glioma and established a PMT-related 10-lncRNA signature for glioma that could independently predict glioma survival and trigger PMT, which enhanced immunosuppression.
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Glioblastoma , Glioma , RNA Longo não Codificante , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Prognóstico , RNA Longo não Codificante/genéticaRESUMO
Age at primary infection with respiratory syncytial virus (RSV) is a crucial factor in determining the outcome of reinfection. However, how neonatal RSV infection affects the immune system and renders the host more susceptible to reinfection in later life is poorly understood. In the present study, by using BALB/c mice that were first infected with RSV as neonates, the role of γδ T cells in the development of airway inflammation during reinfection in adulthood was investigated. We found that neonatal RSV infection resulted in an aggravated infiltration of mononuclear cells in bronchoalveolar lavage (BAL) fluids, in parallel with a significant increase in the levels of type 2 cytokines in lungs on day 4 after reinfection. Since the numbers of total γδ T cells as well as activated γδ T cells, particularly IL-4-, IL-5-, and IL-13-producing γδ T cells, were enhanced markedly in the lungs of neonatally primed mice, we speculate that γδ T cells might participate in the augmented airway inflammation seen during reinfection. Indeed, depletion of γδ T cells attenuated the severity of lung histopathology during reinfection. Meanwhile, treatment of neonatal mice with anti-TCRδ mAb diminished not only the numbers of neutrophils, eosinophils, and lymphocytes, but also the levels of IL-4, IL-5, and IL-13 in the lungs after reinfection in adulthood, suggesting that γδ T cells, particularly Th2-type γδ T cells might play a critical role in exacerbating the pulmonary tissue pathology during reinfection of adult mice that were first infected as neonates.
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Inflamação/imunologia , Pulmão/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções Respiratórias/imunologia , Subpopulações de Linfócitos T/imunologia , Fatores Etários , Animais , Animais Recém-Nascidos , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Interleucina-13/imunologia , Interleucina-4/imunologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Recidiva , Infecções por Vírus Respiratório Sincicial/patologia , Infecções Respiratórias/virologia , Subpopulações de Linfócitos T/metabolismo , Células Th2/imunologiaRESUMO
The phase behavior of symmetric ABC triple-hydrophilic triblock copolymers in concentrated aqueous solutions is investigated using a simulated annealing technique. Two typical cases, in which the hydrophilicity of the middle B-block is either stronger or weaker than that of the end A- and C-blocks, are studied. In these two cases, a variety of phase diagrams are constructed as a function of the volume fraction of the B-block and the copolymer concentration ([Formula: see text] for both non-frustrated and frustrated copolymers. Structures, such as two-color alternatingly packed cylinders or gyroid, and lamellae-in-lamellae etc. that do not occur in the melt system, are obtained in solutions. Rich phase transition sequences, especially re-entrant phase transitions involving complex continuous networks of alternating gyroid and alternating diamond are observed for a given copolymer with decreasing [Formula: see text] . The difference in hydrophilicity among different blocks can result in inhomogeneous distribution of solvent molecules in the morphology, and with the decrease of [Formula: see text] , the distribution of solvent molecules presents a non-monotonic variation. This results in a non-monotonic variation of the effective volume fraction of each domain with the decrease of [Formula: see text] , which induces the re-entrant phase transitions. The presence of a good solvent for all the blocks can cause changes in the effective segregation strengths between different blocks and also in chain conformations, hence can alter the bulk phases and results in the occurrence of new structures and phase transitions. Especially, structures having A-C interfaces or A-C mixed domains can be obtained even in the non-frustrated copolymer systems, and structures obtained in the frustrated systems may be similar to those obtained in the non-frustrated systems. The window of the alternating gyroid structures may occupy a large part of the phase diagram for non-frustrated copolymers with stronger B-hydrophilicity. This behavior can be used to tune the self-assembled structures of block copolymers.
Assuntos
Interações Hidrofóbicas e Hidrofílicas , Polímeros/química , Água/química , Eletrólitos/química , Modelos Moleculares , Conformação Molecular , Transição de Fase , SoluçõesRESUMO
It is well accepted that vaccination by oral administration has many advantages over injected parenteral immunization. The present study focuses on whether oral vaccination with a DNA vaccine could induce protective immunity against respiratory challenge infection. The M1 gene of influenza A virus was used to construct DNA vaccine using pcDNA 3.1(+) plasmid, a eukaryotic expression vector. The cationic liposomes were used to deliver the constructed DNA vaccine. In vitro and in vivo expression of M1 gene was observed in the cell line and in the intestine of orally vaccinated C57BL/6 mice, respectively. It became clear that this type of oral DNA vaccination was capable of inducing both humoral and cellular immune responses, together with an augmentation of IFN-γ production. In addition, oral vaccination with liposome-encapsulated DNA vaccine could protect the mice against respiratory challenge infection. These results suggest that gastrointestinal tract, a constituent member of the common mucosal immune system, is a potent candidate applicable as a DNA vaccine route against virus respiratory diseases.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Lipossomos/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Administração Oral , Animais , Anticorpos Antivirais/sangue , Modelos Animais de Doenças , Vacinas contra Influenza/genética , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vacinas de DNA/genética , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/imunologiaRESUMO
BACKGROUND: It has been reported that adoptive transfer of γδ T cells increases the cellular infiltration, especially eosinophils, in the lungs of allergic mice, suggesting that γδ T cells may play a proinflammatory role in allergic airway inflammation. Respiratory syncytial virus (RSV) infection can decrease the number of Th2-type γδ T cells. However, the underlying mechanisms remain unknown. METHODS: BALB/c mice were inoculated intranasally with RSV before or after sensitization to OVA. The amounts of Th1/Th2 cytokines as well as the levels of specific antibodies were determined by ELISA. The apoptotic death of pulmonary γδ T cells was analyzed by flow cytometry. RESULTS: Adoptive transfer of γδ T cells increased the production of Th2 cytokines in the lungs and allergy-related antibodies in the serum, further confirming that γδ T cells act as pro-inflammatory cells or a promoter for the development of allergic asthma. RSV infection before sensitization to OVA enhanced apoptotic death of pulmonary γδ T cells. The percentage and absolute number of FasL-expressing γδ T cells in the lungs of allergic mice were elicited significantly by prior RSV infection. Blocking FasL with monoclonal antibody diminished apoptotic death of γδ T cells, suggesting that FasL is important for RSV-induced apoptosis of pulmonary γδ T cells. CONCLUSIONS: This work provides evidence that RSV infection suppresses the subsequent development of OVA-induced allergic responses partly by enhancing FasL-mediated apoptosis of pulmonary γδ T cells.
Assuntos
Proteína Ligante Fas/imunologia , Pneumonia/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/virologia , Alérgenos , Análise de Variância , Animais , Apoptose/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Feminino , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/farmacologia , Pneumonia/fisiopatologia , Distribuição Aleatória , Valores de Referência , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Vírus Sinciciais Respiratórios/patogenicidade , Infecções Respiratórias/imunologia , Infecções Respiratórias/fisiopatologia , Medição de Risco , Sensibilidade e Especificidade , Células Th2/imunologiaRESUMO
Glioblastoma (GBM), known as the most malignant and common primary brain tumor of the central nervous system, has finite therapeutic options and a poor prognosis. Studies have shown that host intestinal microorganisms play a role in the immune regulation of parenteral tumors in a number of different ways, either directly or indirectly. However, the potential impact of gut microbiota on tumor microenvironment, particularly glioma immunological milieu, has not been clarified exactly. In this study, by using an orthotopic GBM model, we found gut microbiota dysbiosis caused by antibiotic cocktail treatment boosted the tumor process in vivo. An obvious change that followed gut microbiota dysbiosis was the enhanced percentage of M2-like macrophages in the TME, in parallel with a decrease in the levels of gut microbial metabolite, short-chain fatty acids (SCFAs) in the blood and tumor tissues. Oral supplementation with SCFAs can increase the proportion of M1-like macrophages in the TME, which improves the outcomes of glioma. In terms of mechanism, SCFAs-activated glycolysis in the tumor-associated macrophages may be responsible for the elevated M1 polarization in the TME. This study will enable us to better comprehend the "gut-brain" axis and be meaningful for the development of TAM-targeting immunotherapeutic strategies for GBM patients.
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BACKGROUND: Pituitary adenoma is one of the most common brain tumors. Most pituitary adenomas are benign and can be cured by surgery and/or medication. However, some pituitary adenomas show aggressive growth with a fast growth rate and are resistant to conventional treatments such as surgery, drug therapy, and radiation therapy. These tumors, referred to as refractory pituitary adenomas, often relapse or regrow in the early postoperative period. The tumor microenvironment (TME) has recently been identified as an important factor affecting the biological manifestations of tumors and acts as the main battlefield between the tumor and the host immune system. MAIN BODY: In this review, we focus on describing TME in pituitary adenomas and refractory pituitary adenomas. Research on the immune microenvironment of pituitary adenomas is currently focused on immune cells such as macrophages and lymphocytes, and extensive research and experimental verifications are still required regarding other components of the TME. In particular, studies are needed to determine the role of the TME in the specific biological behaviors of refractory pituitary adenomas, such as high invasion, fast recurrence rate, and high tolerance to traditional treatments and to identify the mechanisms involved. CONCLUSION: Overall, we summarize the similarities and differences between the TME of pituitary adenomas and refractory pituitary adenomas as well as the changes in the biological behavior of pituitary adenomas that may be caused by the microenvironment. These changes greatly affect the outcome of patients.
Assuntos
Adenoma , Neoplasias Hipofisárias , Microambiente Tumoral , Neoplasias Hipofisárias/terapia , Neoplasias Hipofisárias/patologia , Humanos , Microambiente Tumoral/fisiologia , Microambiente Tumoral/imunologia , Adenoma/terapia , Adenoma/patologia , Animais , Resultado do TratamentoRESUMO
Respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans still remain inconclusive. The association between RSV infection and allergic diseases may be dependent on an atopic background and previous history of RSV infection. It has been reported that RSV infection before sensitization to an allergen decreased the production of Th2-like cytokines in the lung and the levels of allergen-specific Th2-type antibodies in the serum. However, the underlying mechanisms are largely unknown. In the present study, the role of pulmonary γδ T cells in RSV-affected, allergen-induced airway inflammation was investigated. BALB/c mice were sensitized to or challenged with ovalbumin (OVA) and infected with RSV either before or after the sensitization period. It became clear that sensitization and challenge of mice with OVA induced a large influx of γδ T cells to the lungs. However, prior RSV infection inhibited the infiltration of γδ T cells as well as activated γδ T cells, characterized by expression of CD40L or CD69 molecular in the cell surface. Moreover, prior RSV infection elevated the type 1 cytokine gene expression but suppressed type 2 cytokine expression in the lung γδ T cells. Adoptive transfer of γδ T cells from OVA-sensitized and challenged mice increased airway inflammation, suggesting that γδ T cells may play a proinflammatory role in allergic responses. These results described here support the idea of an unknown γδ T cell-dependent mechanism in the regulation of RSV-affected, allergen-induced allergic airway responses.
Assuntos
Hipersensibilidade/imunologia , Tolerância Imunológica , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Serpinas/imunologia , Células Th2/imunologia , Animais , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Ligante de CD40/análise , Citocinas/biossíntese , Feminino , Perfilação da Expressão Gênica , Lectinas Tipo C/análise , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Antígenos de Linfócitos T gama-delta/análise , Vírus Sinciciais Respiratórios/imunologia , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/imunologia , Células Th2/químicaRESUMO
Epithelial-mesenchymal transition (EMT) is a common process during tumor progression and is always related to residual tumor, drug resistance and immune suppression. However, considering the heterogeneity in EMT process, there is still a need to establish robust EMT classification system with reasonable molecular, biological and clinical implications to investigate whether these unfavorable survival factors are common or unique in different individuals. In our work, we classify tumors with four EMT status, that is, EMTlow, EMTmid, EMThigh-NOS (Not Otherwise Specified), and EMThigh-AKT (AKT pathway overactivation) subtypes. We find that EMThigh-NOS subtype is driven by intrinsic somatic alterations. While, EMThigh-AKT subtype is maintained by extrinsic cellular interplay between tumor cells and macrophages in an AKT-dependent manner. EMThigh-AKT subtype is both unresectable and drug resistant while EMThigh-NOS subtype can be treated with cell cycle related drugs. Importantly, AKT activation in EMThigh-AKT not only enhances EMT process, but also contributes to the immunosuppressive microenvironment. By remodeling tumor immune-microenvironment by AKT inhibition, EMThigh-AKT can be treated by immune checkpoint blockade therapies. Meanwhile, we develop TumorMT website ( http://tumormt.neuroscience.org.cn/ ) to apply this EMT classification and provide reasonable therapeutic guidance.
Assuntos
Neoplasias , Transdução de Sinais , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Microambiente Tumoral , Neoplasias/tratamento farmacológico , Imunoterapia , Transição Epitelial-Mesenquimal/fisiologiaRESUMO
Glioblastoma multiforme (GBM) with mesenchymal features exhibits enhanced chemotherapeutic resistance and results in reduced overall survival. Recent studies have suggested that there is a positive correlation between the GBM mesenchymal status and immune cell infiltration. However, the mechanisms by which GBM acquires its mesenchymal features in a tumor immune microenvironment-dependent manner remains unknown. Here, we uncovered a chemerin-mediated autocrine and paracrine network by which the mesenchymal phenotype of GBM cells is strengthened. We identified chemerin as a prognostic secretory protein mediating the mesenchymal phenotype-promoting network between tumor-associated macrophages (TAMs) and tumor cells in GBM. Mechanistically, chemerin promoted the mesenchymal features of GBM by suppressing the ubiquitin-proteasomal degradation of CMKLR1, a chemerin receptor predominantly expressed on TAMs and partially expressed on GBM cells, thereby enhancing NF-κB pathway activation. Moreover, chemerin was found to be involved in the recruitment of TAMs in the GBM tumor microenvironment. We revealed that chemerin also enhances the mesenchymal phenotype-promoting ability of TAMs and promotes their M2 polarization via a CMKLR1/NF-κB axis, which further exacerbates the mesenchymal features of GBM. Blocking the chemerin/CMKLR1 axis with 2-(α-naphthoyl) ethyltrimethylammonium iodide disrupted the mesenchymal network and suppressed tumor growth in GBM. These results suggest the therapeutic potential of targeting the chemerin/CMKLR1 axis to block the mesenchymal network in GBM.
Assuntos
Quimiocinas/metabolismo , Glioblastoma , Comunicação Autócrina , Quimiocinas/genética , Glioblastoma/patologia , Humanos , NF-kappa B , Comunicação Parácrina , Receptores de Quimiocinas , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
The tumor microenvironment (TME) plays a critical role in promoting the growth and metastasis of glioblastoma (GBM). Tumor-associated macrophages (TAMs), the most abundant myeloid cells infiltrating in TME, produce proinflammatory cytokines, regulate glioma cell pools, and lead to GBM progression. Understanding the mechanism of GBM-TAMs regulation can help to find new targeted therapeutic strategies against GBM. Based on the CGGA and TCGA GBM cohorts, ARPC1B was defined as the key macrophage-associated gene with prognostic value. Higher ARPC1B expression was associated with progressive malignancy, poor outcomes and TAM infiltration. We demonstrated that macrophage-expressed ARPC1B promoted the migration, invasion, and epithelial-mesenchymal transition of glioma cells. Glioma-intrinsic ARPC1B also maintained the malignant phenotype and promoted macrophage recruitment. Positive feedback signaling between macrophages and glioma cells via ARPC1B was determined to be under control of the IFNγ-IRF2-ARPC1B axis. This study highlights the important role of ARPC1B in GBM malignancy progression and the regulation network between GBM and TAMs, suggesting ARPC1B as a novel biomarker with potential therapeutic implications.
Assuntos
Glioblastoma , Glioma , Complexo 2-3 de Proteínas Relacionadas à Actina , Linhagem Celular Tumoral , Glioblastoma/genética , Humanos , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
Tumor protein 53 mutation (TP53mut) is one of the most important driver events facilitating tumorigenesis, which could induce a series of chain reactions to promote tumor malignant transformation. However, the malignancy progression patterns under TP53 mutation remain less known. Clarifying the molecular landscapes of TP53mut tumors will help us understand the process of tumor development and aid precise treatment. Here, we distilled genetic and epigenetic features altered in TP53mut cancers for cluster-of-clusters analysis. Using integrated classification, we derived 5 different subtypes of TP53mut patients. These subtypes have distinct features in genomic alteration, clinical relevance, microenvironment dysregulation, and potential therapeutics. Among the 5 subtypes, COCA3 was identified as the subtype with worst prognosis, causing an immunosuppressive microenvironment and immunotherapeutic resistance. Further drug efficacy research highlighted olaparib as the most promising therapeutic agents for COCA3 tumors. Importantly, the therapeutic efficacy of olaparib in COCA3 and immunotherapy in non-COCA3 tumors was validated via in vivo experimentation. Our study explored the important molecular events and developed a subtype classification system with distinct targeted therapy strategies for different subtypes of TP53mut tumors. These multiomics classification systems provide a valuable resource that significantly expands the knowledge of TP53mut tumors and may eventually benefit in clinical practice.
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Genômica , Neoplasias , Humanos , Epigenômica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment, and immunotherapy is still poorly understood. METHODS: Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components, and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma. RESULTS: Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes, and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand-1 (PD-L1) blockade generated a synergistic therapeutic outcome in GBM murine models. CONCLUSIONS: This work provides a molecular, clinical, and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade treatment with ferroptosis inhibition.
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Ferroptose , Glioblastoma , Glioma , Animais , Apoptose , Glioblastoma/patologia , Glioma/patologia , Terapia de Imunossupressão , Imunoterapia , Camundongos , Microambiente TumoralRESUMO
Inflammasome signaling is a reaction cascade that influences immune response and cell death. Although the inflammasomes participate in tumorigenesis, their role as an oncogenic booster or a tumor suppresser is still controversial. Therefore, it is important to comprehensively investigate the inflammasome signaling status across various cancers to clarify its clinical and therapeutic significance. Methods: A total of 9881 patients across 33 tumor types from The Cancer Genome Atlas database were included in this study. Five gene sets were identified to step-wisely profile inflammasome signaling. Unsupervised clustering was used for sample classification based on gene set enrichment. Machine learning and in vitro and in vivo experiments were used to confirm the implications of inflammasome classification. Results: A hundred and forty-one inflammasome-signaling-related genes were identified to construct five gene sets representing the sensing, activation, and termination steps of the inflammasome signaling. Six inflammasome clusters were robustly established with distinct molecular, biological, clinical, and therapeutic features. Importantly, clusters with inflammasome signaling activation were found to be immunosuppressive and resistant to ICB treatment. Inflammasome inhibition reverted the therapeutic failure of ICB in inflammasome-activated tumors. Moreover, based on the proposed classification and therapeutic implications, an open website was established to provide tumor patients with comprehensive information on inflammasome signaling. Conclusions: Our study conducted a systematical investigation on inflammasome signaling in various tumor types. These findings highlight the importance of inflammasome evaluation in tumor classification and provide a foundation for improving relevant therapeutic regimens.
Assuntos
Inflamassomos/imunologia , Neoplasias/metabolismo , Transdução de Sinais/genética , Biomarcadores Tumorais/genética , Carcinogênese/genética , China , Bases de Dados Genéticas , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Humanos , Fatores Imunológicos/genética , Imunoterapia/métodos , Inflamassomos/metabolismo , Neoplasias/classificação , Neoplasias/imunologia , Prognóstico , Transdução de Sinais/imunologia , Transcriptoma/genética , Microambiente Tumoral/imunologiaRESUMO
Background: Abnormal redox equilibrium is a major contributor to tumor malignancy and treatment resistance. Understanding reactive oxygen species (ROS) metabolism is a key to clarify the tumor redox status. However, we have limited methods to evaluate ROS in tumor tissues and little knowledge on ROS metabolism across human cancers. Methods: The Cancer Genome Atlas multi-omics data across 22 cancer types and the Genomics of Drug Sensitivity in Cancer data were analyzed in this study. Cell viability testing and xenograft model were used to validate the role of ROS modulation in regulating treatment efficacy. Results: ROS indexes reflecting ROS metabolic balance in five dimensions were developed and verified. Based on the ROS indexes, we conducted ROS metabolic landscape across 22 cancer types and found that ROS metabolism played various roles in different cancer types. Tumor samples were classified into eight ROS clusters with distinct clinical and multi-omics features, which was independent of their histological origin. We established a ROS-based drug efficacy evaluation network and experimentally validated the predicted effects, suggesting that modulating ROS metabolism improves treatment sensitivity and expands drug application scopes. Conclusion: Our study proposes a new method in evaluating ROS status and offers comprehensive understanding on ROS metabolic equilibrium in human cancers, which provide practical implications for clinical management.
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CD4+T cells are crucial cellular source of type 2 cytokines and responsible for RSV-induced asthma-like symptoms and asthma exacerbations. However, the mechanism for regulating the activation of CD4+T cells during RSV infection is not clear completely. We show in this study that infection with RSV may induce an expansion and activation of CD4+T cells in the lungs of BALB/c mice. RSV-induced CD4+T cell expansion and activation seems to depend upon the pulmonary group 2 innate lymphoid cells (ILC2s), since adoptive transfer of lung ILC2s can enhance not only the numbers of CD4+T cells but also the cytokine production by CD4+T cells. Interestingly, blockade of the contact between ILC2s and CD4+T cells, may significantly diminish the CD4+T cell expansion and cytokine production, suggesting that membrane molecules may be involved in ILC2-regulated CD4+T cell activation. In fact, infection with RSV resulted in an increase in the numbers of OX40+CD4+T cells as well as OX40L+ILC2s in the lungs of mice. Moreover, the mRNA expressions of OX40 and OX40L as well as the levels of OX40 and OX40L proteins in the lung CD4+T cells and ILC2s were elevated respectively. When co-culture of CD4+T cells with ILC2s in the presence of anti-OX40L antibody, the cytokine productions by CD4+T cells were reduced markedly, suggesting that lung ILC2s may regulate RSV-induced CD4+T cell expansion and activation perhaps via OX40/OX40L interaction.
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Pulmão/citologia , Pulmão/imunologia , Linfócitos/imunologia , Ligante OX40/imunologia , Receptores OX40/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Técnicas de Cocultura , Citocinas/imunologia , Feminino , Imunidade Inata , Camundongos Endogâmicos BALB C , Baço/citologiaRESUMO
The mechanisms of magnetoreception have been proposed as the magnetite-based, the chemical radical-pair and biocompass model, in which magnetite particles, the cryptochrome (Cry) or iron-sulfur cluster assembly 1 (IscA1) may be involved. However, little is known about the association among the molecules. Here we investigated the molecular characterization and the mRNA expression of IscA1 in different developmental stages, tissues and magnetic fields in the migratory brown planthopper (BPH), Nilaparvata lugens. NlIscA1 contains an open reading frame of 390 bp, encoding amino acids of 129, with the predicted molecular weight of 14.0 kDa and the isoelectric point of 9.10. Well-conserved Fe-S cluster binding sites were observed in the predicted protein. Phylogenetic analysis demonstrated NlIscA1 to be clustered into the insect's IscA1. NlIscA1 showed up-regulated mRNA expression during the period of migration. The mRNA expression of NlIscA1 could be detected in all the three tissues of head, thorax and abdomen, with the highest expression level in the abdomen. For the macropterous migratory Nilaparvata lugens, mRNA expression of NlIscA1 and N. lugens cryptochrome1 (Nlcry1) were up-regulated under the magnetic fields of 5 Gauss and 10 Gauss in strength (vs. local geomagnetic field), while N. lugens cryptochrome2 (Nlcry2) remained stable. For the brachyterous non-migratory Nilaparvata lugens, no significant changes were found in mRNA expression of NlIscA1, Nlcry1 and Nlcry2 among different magnetic fields. These findings preliminarily reveal that the expression of NlIscA1 and Nlcry1 exhibited coordinated responses to the magnetic field. It suggests some potential associations among the putative magneto-sensitive molecules of cryptochrome and iron-sulfur cluster assembly.
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Hemípteros/metabolismo , Proteínas Ferro-Enxofre/metabolismo , Sequência de Aminoácidos , Animais , Criptocromos/metabolismo , Hemípteros/genética , Hemípteros/crescimento & desenvolvimento , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Proteínas Ferro-Enxofre/genética , Campos Magnéticos , Filogenia , Asas de AnimaisRESUMO
Infection with respiratory syncytial virus (RSV) in neonatal mice causes more aggressive airway disease when the mice are reinfected with the same virus as adults. However, the underlying mechanisms responsible for this phenomenon are not entirely defined. Natural helper (NH) cells are considered a key factor for virus-induced or exacerbated airway inflammation and airway hyper-responsiveness by producing type 2 cytokines. To confirm whether NH cells are involved in the aggravated lung pathology seen during reinfection, BALB/c mice were initially infected as neonates and reinfected in adulthood. We observed that neonatal RSV infection resulted in an enhanced infiltration of eosinophils and neutrophils in the lungs, in parallel with a significant increase in the levels of IL-5 and IL-13 in bronchoalveolar lavage fluids on day 2 after reinfection. It seems likely that pulmonary NH cells may play a role in the occurrence, since mice first infected at 1wk of age developed an additional increase in the number of NH cells as well as IL-5- and IL-13-producing NH cells in the lungs than those first infected as young adults. In fact, an elevated expression of mRNAs for IL-5 and IL-13 in pulmonary NH cells was detected in mice first infected as neonates. Furthermore, adoptive transfer of NH cells into neonatal mice was able to boost eosinophilic infiltration as well as the production of type 2 cytokines in the lungs after reinfection at adulthood. In contrast, the expression of mRNA for the type 1 cytokine IFN-γ was down-regulated markedly by adoptive transfer of NH cells. Thus, these results suggest that Th2-type NH cells may play a role in the exacerbated airway inflammation seen during RSV reinfection of neonatally primed mice.
Assuntos
Inflamação/imunologia , Pulmão/patologia , Hipersensibilidade Respiratória/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Células Th2/imunologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Regulação da Expressão Gênica , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-5/genética , Interleucina-5/metabolismo , Camundongos , Camundongos Endogâmicos BALB CRESUMO
It has been reported that natural helper cells, which are a non-T, non-B innate lymphoid cell type expressing c-Kit and ST2, mediate influenza-induced airway hyper-reactivity by producing substantial IL-13. However, little is known about natural helper cells for the development of RSV-induced airway inflammation, particularly eosinophilic infiltration. By using BALB/c mice that were infected intranasally with RSV, it became clear that infection with RSV can induce an increase in the absolute number of natural helper cells in the lungs of mice. It seems likely that these natural helper cells contribute to the massive eosinophilic infiltration in an IL-13-dependent manner. In fact, the number of IL-13-producing natural helper cells as well as the expression of IL-13 mRNA in natural helper cells was enhanced significantly during RSV infection, suggesting that natural helper cells might be cellular source of the Th2-type cytokine IL-13. Indeed, adoptive transfer of pulmonary natural helper cells augmented not only the production of IL-13 but also the infiltration of eosinophils in the lungs of transferred mice. Pulmonary natural helper cells can produce IL-13 following response to IL-33, which was increased markedly in the lungs of mice after intranasal RSV infection. The expression of IL-13 mRNA in pulmonary natural helper cells was up-regulated by in vitro IL-33 stimulation. Furthermore, blockade of IL-33 receptor subunit, ST2, diminished the frequency of IL-13-producing natural helper cells. Taken together, these results demonstrate that natural helper cells may play an important role in RSV-induced pulmonary eosinophilia by producing IL-13 via the IL-33/ST2 pathway.