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BACKGROUND: Molecularly targeted therapies have recently become a hotspot in the treatment of LUAD, with ongoing efforts to identify new effective targets due to individual variability. Among these potential targets, the mitochondrial transcription elongation factor (TEFM) stands out as a crucial molecule involved in mitochondrial synthetic transcriptional processing. Dysregulation of TEFM has been implicated in the development of various diseases; however, its specific role in LUAD remains unclear. METHODS: We conducted a comprehensive analysis of TEFM expression in LUAD, leveraging data from the TCGA database. Subsequently, we validated these findings using clinical specimens obtained from the First Affiliated Hospital of Soochow University, employing western blotting and qRT-PCR techniques. Further experimental validation was performed through the transfection of cells with TEFM overexpression, knockdown, and knockout lentiviruses. The effects of TEFM on LUAD were evaluated both in vitro and in vivo using a range of assays, including CCK-8, colony formation, EdU incorporation, Transwell migration, Tunel assay, flow cytometry, JC-1 staining, and xenograft tumour models. RESULTS: Our investigation uncovered that TEFM exhibited elevated expression levels in LUAD and exhibited co-localization with mitochondria. Overexpression of TEFM facilitated malignant processes in LUAD cells, whereas its silencing notably curbed these behaviors and induced mitochondrial depolarization, along with ROS production, culminating in apoptosis. Moreover, the absence of TEFM substantially influenced the expression of mitochondrial transcripts and respiratory chain complexes. Results from nude mouse xenograft tumors further validated that inhibiting TEFM expression markedly hindered tumor growth. CONCLUSION: TEFM promotes LUAD malignant progression through the EMT pathway and determines apoptosis by affecting the expression of mitochondrial transcripts and respiratory chain complexes, providing a new therapeutic direction for LUAD-targeted therapy.
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Apoptosis , Mitocondrias , Factores de Elongación Transcripcional , Humanos , Animales , Mitocondrias/metabolismo , Línea Celular Tumoral , Factores de Elongación Transcripcional/metabolismo , Factores de Elongación Transcripcional/genética , Apoptosis/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Movimiento Celular , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones , Especies Reactivas de Oxígeno/metabolismo , Terapia Molecular Dirigida , Femenino , MasculinoRESUMEN
Motion retargeting for animation characters has potential applications in fields such as animation production and virtual reality. However, current methods either assume that the source and target characters have the same skeletal structure, or require designing and training specific model architectures for each structure. In this paper, we aim to address the challenge of motion retargeting across previously unseen skeletal structures with a unified dynamic graph network. The proposed approach utilizes a dynamic graph transformation module to dynamically transfer latent motion features to different structures. We also take into consideration for intricate hand movements and model both torso and hand joints as graphs in a unified manner for whole-body motion retargeting. Our model allows the use of motion data from different structures to train a unified model and learns cross-structural motion retargeting in an unsupervised manner with unpaired data. Experimental results demonstrate the superiority of the proposed method in terms of data efficiency and performance on both seen and unseen structures.
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The current evidence provides support for the involvement of bone marrow mesenchymal stem cells (BMSCs) in the regulation of airway epithelial cells. However, a comprehensive understanding of the underlying biological mechanisms remains elusive. This study aimed to isolate and characterize BMSC-derived exosomes (BMSC-Exos) and epithelial cells (ECs) through primary culture. Subsequently, the impact of BMSC-Exos on ECs was assessed in vitro, and sequencing analysis was conducted to identify potential molecular mechanisms involved in these interactions. Finally, the efficacy of BMSC-Exos was evaluated in animal models in vivo. In this study, primary BMSCs and ECs were efficiently isolated and cultured, and high-purity Exos were obtained. Upon uptake of BMSC-Exos, ECs exhibited enhanced proliferation (p < .05), while migration showed no difference (p > .05). Notably, invasion demonstrated significant difference (p < .05). Sequencing analysis suggested that miR-21-5p may be the key molecule responsible for the effects of BMSC-Exos, potentially mediated through the MAPK or PI3k-Akt signaling pathway. The in vivo experiments showed that the presence of methacrylated gelatin (GelMA) loaded with BMSC-Exos in composite scaffold significantly enhanced epithelial crawling in the patches in comparison to the pure decellularized group. In conclusion, this scheme provides a solid theoretical foundation and novel insights for the research and clinical application of tracheal replacement in the field of tissue engineering.
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Células Epiteliales , Exosomas , Gelatina , Células Madre Mesenquimatosas , Andamios del Tejido , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Exosomas/metabolismo , Gelatina/química , Gelatina/farmacología , Animales , Andamios del Tejido/química , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humanos , Metacrilatos/química , MicroARNs/genética , MicroARNs/metabolismo , Proliferación Celular/efectos de los fármacos , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Células Cultivadas , Masculino , Movimiento Celular/efectos de los fármacosRESUMEN
Background: Angiogenesis stands as a pivotal hallmark in lung adenocarcinoma (LUAD), intricately shaping the tumor microenvironment (TME) and influencing LUAD progression. It emerges as a promising therapeutic target for LUAD, affecting patients' prognosis. However, its role in TME, LUAD prognosis, and its clinical applicability remain shrouded in mystery. Methods: We employed integrated single-cell and bulk transcriptome sequencing to unravel the heterogeneity of angiogenesis within LUAD cells. Through "consensus clustering", we delineated distinct angiogenic clusters and deciphered their TME features. "Monocle2" was used to unravel divergent trajectories within malignant cell subpopulations of LUAD. Additionally, regulon submodules and specific cellular communication patterns of cells in different angiogenic states were analyzed by "pyscenic" and "Cellchat" algorithms. The "univariate Cox" and "LASSO" algorithms were applied to build angiogenic prognostic models. Immunohistochemistry (IHC) on clinical samples validated the role of model factors in LUAD angiogenesis. We utilized CTRP 2.0 and PRISM databases for pinpointing sensitive drugs against lung adenocarcinoma. Results: Two clusters for the activation of angiogenesis were identified, with Cluster 1 showing a poor prognosis and a pro-cancerous TME. Three differentiated states of malignant epithelial LUAD cells were identified, which had different degrees of angiogenic activation, were regulated by three different regulon submodules, and had completely different crosstalk from other cells in TME. The experiments validate that SLC2A1 promotes angiogenesis in LUAD. ARS (Angiogenesis related score) had a high prognostic value; low ARSs showed immunotherapy benefits, whereas high ARSs were sensitive to 15 chemotherapeutic agents. Conclusion: The assessment of angiogenic clusters helps to determine the prognostic and TME characteristics of LUAD. Angiogenic prognostic models can be used to assess the prognosis, immunotherapeutic response, and chemotherapeutic drug sensitivity of LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , RNA-Seq , Pronóstico , Comunicación Celular , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Microambiente Tumoral/genéticaRESUMEN
Lung adenocarcinoma (LUAD) remains one of the most lethal malignancies worldwide, with a high mortality rate and unfavorable prognosis. Endoplasmic reticulum (ER) stress is a key regulator of tumour growth, metastasis, and the response to chemotherapy, targeted therapies and immune response. It acts via responding to misfolded proteins and triggering abnormal activation of ER stress sensors and downstream signalling pathways. Notably, the expression patterns of ER-stress-related-genes (ERSRGs) are indicative of survival outcomes, especially in the context of immune infiltration. Through consensus clustering of prognosis-associated ERSRGs, we delineated two distinct LUAD subtypes: Cluster 1 and Cluster 2. Comprehensive analyses revealed significant disparities between these subtypes in terms of prognosis, immune cell infiltration, and tumor progression. Leveraging the robustness of LASSO regression and Multivariate stepwise regression, we constructed and validated an ER Stress-associated risk signature for LUAD. This signature underwent assessments for its prognostic value, correlation with clinical attributes, and interaction within the tumour immune microenvironment. By integrating this signature with multivariate cox analysis of distinct pathological stages, we devised an enhanced nomogram, validated through various statistical metrics, with an area under the curve for overall survival at 1, 3, and 5 years post-diagnosis being 0.79, 0.80, and 0.81, respectively. In conclusion, our findings introduce a composite signature of 11 pivotal ERSRGs, holding promise as a potent prognostic tool for LUAD, and offering insights for immunotherapeutic and targeted intervention strategies.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Microambiente Tumoral/genética , Pronóstico , Adenocarcinoma del Pulmón/genética , Estrés del Retículo Endoplásmico , Neoplasias Pulmonares/genéticaRESUMEN
Background: Lung adenocarcinoma (LUAD) is a major subtype of non-small cell lung cancer (NSCLC) with a highly heterogeneous tumor microenvironment. Immune checkpoint inhibitors (ICIs) are more effective in tumors with a pre-activated immune status. However, the potential of the immune activation-associated gene (IAG) signature for prognosis prediction and immunotherapy response assessment in LUAD has not been established. Therefore, it is critical to explore such gene signatures. Methods: RNA sequencing profiles and corresponding clinical parameters of LUAD were extracted from the TCGA and GEO databases. Unsupervised consistency clustering analysis based on immune activation-related genes was performed on the enrolled samples. Subsequently, prognostic models based on genes associated with prognosis were built using the last absolute shrinkage and selection operator (LASSO) method and univariate Cox regression. The expression levels of four immune activation related gene index (IARGI) related genes were validated in 12 pairs of LUAD tumor and normal tissue samples using qPCR. Using the ESTIMATE, TIMER, and ssGSEA algorithms, immune cell infiltration analysis was carried out for different groups, and the tumor immune dysfunction and rejection (TIDE) score was used to evaluate the effectiveness of immunotherapy. Results: Based on the expression patterns of IAGs, the TCGA LUAD cohort was classified into two clusters, with those in the IAG-high pattern demonstrating significantly better survival outcomes and immune cell infiltration compared to those in the IAG-low pattern. Then, we developed an IARGI model that effectively stratified patients into different risk groups, revealing differences in prognosis, mutation profiles, and immune cell infiltration within the tumor microenvironment between the high and low-risk groups. Notably, significant disparities in TIDE score between the two groups suggest that the low-risk group may exhibit better responses to ICIs therapy. The IARGI risk model was validated across multiple datasets and demonstrated exceptional performance in predicting overall survival in LUAD, and an IARGI-integrated nomogram was established as a quantitative tool for clinical practice. Conclusion: The IARGI can serve as valuable biomarkers for evaluating the tumor microenvironment and predicting the prognosis of LUAD patients. Furthermore, these genes probably provide valuable guidance for establishing effective immunotherapy regimens for LUAD patients.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/terapia , Pronóstico , Inmunoterapia , Microambiente Tumoral/genéticaRESUMEN
Background: The FHL family (four-and-a-half-LIM-only protein family) contains five multifunctional proteins (FHL1-5) that are involved in cell survival, transcriptional regulation, and signal transduction. Among these proteins, FHL2 is one of the most reported members in tumors, which is differentially expressed in numerous tumors. However, no systematic pan-cancer analysis of FHL2 has been performed so far. Methods: We obtained The Cancer Genome Atlas (TCGA) expression profiles and clinical data from Xena database and the Tumor Immune Estimation Resource (TIMER) database. Gene expression, prognosis, mRNA modification, and immune infiltration of FHL2 in pan-cancer were analyzed. Functional analysis validated the potential mechanism of FHL2 in lung adenocarcinoma (LUAD). Results: FHL2 is differentially expressed in a wide range of tumors and has prognostic value. Digging into the immune landscape of FHL2, we found that FHL2 is significantly associated with tumor-associated fibroblasts. Furthermore, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) suggested that FHL2 may be involved in epithelial-mesenchymal transition (EMT)-associated pathways such as NF-KB and TGF-ß in LUAD. Conclusions: Our comprehensive bioinformatics analysis identified mRNA level expression of FHL2 correlates with prognosis in different cancers. This study may help to more fully explore the role of FHL2 in tumor progression and metastasis.
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Background: Recent studies have revealed that SUMOylation modifications are involved in various biological processes, including cancer development and progression. However, the precise role of SUMOylation in lung adenocarcinoma (LUAD), especially in the tumor immune microenvironment, is not yet clear. Methods: We identified SUMOylation patterns by unsupervised consensus clustering based on the expression of SUMOylation regulatory genes. The tumor microenvironment in lung adenocarcinoma was analyzed using algorithms such as GSVA and ssGSEA. Key genes of SUMOylation patterns were screened for developing a SUMOylation scoring model to assess immunotherapy and chemotherapy responses in lung adenocarcinoma patients. Experiments were conducted to validate the differential expression of model genes in lung adenocarcinoma. Finally, we constructed a nomogram based on the SUMOylation score to assess the prognosis of individual lung adenocarcinoma patients. Results: Two patterns of SUMOylation were identified, namely, SUMO-C1, which showed anti-tumor immune phenotype, and SUMO-C2, which showed immunosuppressive phenotype. Different genomic subtypes were also identified; subtype gene-T1 exhibited a reciprocal restriction between the immune microenvironment and stromal microenvironment. High SUMOylation scores were indicative of poor lung adenocarcinoma prognosis. SUMOylation score was remarkably negatively correlated with the infiltration of anti-tumor immune cells, and significantly positively correlated with immune cells promoting immune escape and immune suppression. In addition, patients with low scores responded better to immunotherapy. Therefore, the developed nomogram has a high prognostic predictive value. Conclusion: The SUMOylation patterns can well discriminate the tumor microenvironment features of lung adenocarcinoma, especially the immune cell infiltration status. The SUMOylation score can further assess the relationship between SUMOylation and immune cell crosstalk and has significant prognostic value and can be used to predict immunotherapy and chemotherapy response in patients with lung adenocarcinoma.
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COVID-19 , Trastornos Mentales , Humanos , Salud Mental , Cuarentena , Trastornos Mentales/epidemiología , Ansiedad , Depresión/epidemiologíaRESUMEN
Background: Tumor-associated macrophages as important members of the tumor microenvironment, are highly plastic and heterogeneous. TAMs can be classified into two preliminary subtypes: M1 and M2 macrophages. M2 macrophages are significantly associated with the progression of lung adenocarcinoma. However, no study has investigated the heterogeneity among M2 macrophages and their differentiation-related genes at the single-cell level to guide the clinical treatment of lung adenocarcinoma. Methods: Using the available annotation information from the Tumor Immune Single-cell Hub database, we clustered and annotated 12 lung adenocarcinoma samples using the R package 'Seurat'. Subsequently, we extracted M2 macrophages for secondary clustering analysis and performed cell trajectory analysis using the R package 'monocle2'. Based on heterogeneous genes associated with the differentiation trajectory of M2 macrophages, we established a prognostic lung adenocarcinoma model using Lasso-Cox and multivariate stepwise regression. In addition, we also performed immunotherapy and chemotherapy predictions. Results: M2 macrophages exhibit heterogeneity among themselves. M2 macrophages in different differentiation states showed significant differences in pathway activation and immune cell communication. Prognostic signature based on heterogeneous genes can be used to classify the prognostic status and abundance of immune cell infiltration in lung adenocarcinoma patients. In addition, the calculation of the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the validation of the GSE126044 database indicated that lung adenocarcinoma patients with high-risk scores had poorer treatment outcomes when receiving immune checkpoint inhibitors treatment. Conclusion: Based on scRNA-seq and Bulk-seq data, we identified M2 macrophage-associated prognostic signature with a potential clinical utility to improve precision therapy.
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Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer with a complex tumor microenvironment. Neddylation, as a type of post-translational modification, plays a vital role in the development of LUAD. To date, no study has explored the potential of neddylation-associated genes for LUAD classification, prognosis prediction, and treatment response evaluation. Methods: Seventy-six neddylation-associated prognostic genes were identified by Univariate Cox analysis. Patients with LUAD were classified into two patterns based on unsupervised consensus clustering analysis. In addition, a 10-gene prognostic signature was constructed using LASSO-Cox and a multivariate stepwise regression approach. Results: Substantial differences were observed between the two patterns of LUAD in terms of prognosis. Compared with neddylation cluster2, neddylation cluster1 exhibited low levels of immune infiltration that promote tumor progression. Additionally, the neddylation-related risk score correlated with clinical parameters and it can be a good predictor of patient outcomes, gene mutation levels, and chemotherapeutic responses. Conclusion: Neddylation patterns can distinguish tumor microenvironment and prognosis in patients with LUAD. Prognostic signatures based on neddylation-associated genes can predict patient outcomes and guide personalized treatment.
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BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and has a poor prognosis. RBR E3 ubiquitin ligases are a special class of E3 ubiquitin ligases which contain three zinc-bing domains that catalyze ubiquitin to substrate proteins. The RBR family of E3 ubiquitin ligases has been reported in various human malignancies, but the roles of RBR E3 ubiquitin ligases in LUAD remain unclear. METHODS: By using TCGA and Kaplan-Meier plotter databases, we examined the expression and prognostic value of RBR E3 ubiquitin ligases. cBioPortal was used to analyze genetic mutations. The STRING database was used to build a protein interactive network. GO, KEGG, and GSEA were performed to investigate the potential biological functions of RBR E3 ubiquitin ligases. RESULTS: The expression of ARIH2, RNF144B, RNF216, and RNF217 was significantly related to the clinicopathological parameters and prognosis in LUAD patients. GSEA enrichment result showed ARIH2, RNF144B, RNF216, and RNF217 were all associated with NADH dehydrogenase complex assembly. GO functional enrichment analysis revealed that four RBR E3 ubiquitin ligases and their interactors were most correlated with ubiquitin-protein transferase activity. KEGG pathway analysis indicated they were associated with cytosolic DNA-sensing pathway, RIG-I-like receptor signaling pathway and NF-kappa B signaling pathway. CONCLUSIONS: Our comprehensive bioinformatic analysis revealed that ARIH2, RNF144B, RNF216, and RNF217 may be new prognostic biomarkers and these findings will help to better understand the distinct roles of RBR E3 ubiquitin ligases in LUAD.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Humanos , Neoplasias Pulmonares/genética , Pronóstico , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinasRESUMEN
Lung adenocarcinoma (LUAD) is one of the most common malignancies with the highest mortality globally, and it has a poor prognosis. Cell cycle checkpoints play a central role in the entire system of monitoring cell cycle processes, by regulating the signalling pathway of the cell cycle. Cell cycle checkpoints related genes (CCCRGs) have potential utility in predicting survival, and response to immunotherapies and chemotherapies. To examine this, based on CCCRGs, we identified two lung adenocarcinoma subtypes, called cluster1 and cluster2, by consensus clustering. Enrichment analysis revealed significant discrepancies between the two subtypes in gene sets associated with cell cycle activation and tumor progression. In addition, based on Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, we have developed and validated a cell cycle checkpoints-related risk signature to predict prognosis, tumour immune microenvironment: (TIME), immunotherapy and chemotherapy responses for lung adenocarcinoma patients. Results from calibration plot, decision curve analysis (DCA), and time-dependent receiver operating characteristic curve (ROC) revealed that combining age, gender, pathological stages, and risk score in lung adenocarcinoma patients allowed for a more accurate and predictive nomogram. The area under curve for lung adenocarcinoma patients with 1-, 3-, 5-, and 10-year overall survival was: 0.74, 0.73, 0.75, and 0.81, respectively. Taken together, our proposed 4-CCCRG signature can serve as a clinically useful indicator to help predict patients outcomes, and could provide important guidance for immunotherapies and chemotherapies decision for lung adenocarcinoma patients.
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BACKGROUND: Cystatins are a class of proteins that can inhibit cysteine protease and are widely distributed in human bodily fluids and secretions. Cystatin SN (CST1), a member of the CST superfamily, is abnormally expressed in a variety of tumors. However, its effect on the occurrence and development of lung adenocarcinoma (LUAD) remains unclear. METHODS: We obtained transcriptome analysis data of CST1 from The Cancer Genome Atlas (TCGA) and GSE31210 databases. The association of CST1 expression with prognosis, gene mutations and tumor immune microenvironment was analyzed using public databases. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed to investigate the potential mechanisms of CST1. RESULTS: In this study, we found that CST1 was highly expressed in lung adenocarcinoma and was associated with prognosis and tumor immune microenvironment. Genetic mutations of CST1 were shown to be related to disease-free survival (DFS) by using the c-BioPortal tool. Potential proteins binding to CST1 were identified by constructing a protein-protein interaction (PPI) network. Gene set enrichment analysis (GSEA) of CST1 revealed that CST1 was notably enriched in epithelial-mesenchymal transition (EMT). Cell experiments confirmed that overexpression of CST1 promoted lung adenocarcinoma cells migration and invasion, while knockdown of CST1 significantly inhibited lung adenocarcinoma cells migration and invasion. CONCLUSIONS: Our comprehensive bioinformatics analyses revealed that CST1 may be a novel prognostic biomarker in LUAD. Experiments confirmed that CST1 promotes epithelial-mesenchymal transition in LUAD cells. These findings will help to better understand the distinct role of CST1 in LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Biomarcadores , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Pronóstico , Cistatinas Salivales/genética , Cistatinas Salivales/metabolismo , Microambiente Tumoral/genéticaAsunto(s)
Trastornos de Ansiedad/epidemiología , Infecciones por Coronavirus/epidemiología , Trastorno Depresivo/epidemiología , Personal de Salud/estadística & datos numéricos , Neumonía Viral/epidemiología , Cuarentena/estadística & datos numéricos , Adulto , Ansiedad/epidemiología , Ansiedad/psicología , Trastornos de Ansiedad/psicología , Betacoronavirus , COVID-19 , Estudios de Casos y Controles , China/epidemiología , Depresión/epidemiología , Depresión/psicología , Trastorno Depresivo/psicología , Femenino , Personal de Salud/psicología , Humanos , Modelos Logísticos , Masculino , Trastornos Mentales/epidemiología , Persona de Mediana Edad , Aplicaciones Móviles , Pandemias , Cuestionario de Salud del Paciente , Prevalencia , Cuarentena/psicología , SARS-CoV-2 , Encuestas y CuestionariosRESUMEN
Progression or recurrence due to resistance to aromatase inhibitors (AIs) is a significant clinical problem for a considerable number of patients with breast cancer. Programmed cell death 4 (PDCD4), a tumor suppressor protein, is targeted for degradation during tumor progression. In the current study, we aimed to examine PDCD4 expression and regulation in AI-resistant breast cancer cells, and its association with survival in patients with estrogen receptor (ER)-positive breast cancer. We determined PDCD4 expression levels in AI-resistant breast cancer cell lines and ER-positive breast cancer tumors, investigated the regulation of PDCD4 in AI-resistant breast cancer cell lines, and carried out a Kaplan-Meier survival analysis in two independent cohorts that included a total of 420 patients with ER-positive breast cancer. We found that PDCD4 expression was down-regulated in AI-resistant breast cancer cells, and this down-regulation was inversely correlated with activation of HER2 signaling. Moreover, lower expression of PDCD4 was significantly associated with HER2 positive status in ER-positive breast tumors. Down-regulation of PDCD4 was mediated through up-regulation of HER2 via the mitogen-activated protein kinase (MAPK), protein kinase B (PKB/AKT), and miR-21 in AI-resistant breast cancer cells. MiR-21 inhibitor and the ER down-regulator fulvestrant induced PDCD4 expression and decreased cell proliferation in AI-resistant breast cancer cells. Furthermore, forced overexpression of PDCD4 resensitized AI-resistant cells to AI or hormone deprivation. Finally, we identified that down-regulation of PDCD4 was associated with a lower rate of disease-free survival in patients with ER-positive breast cancer and high histologic grade of breast tumors. In summary, our study shows that expression of PDCD4 is down-regulated by HER2 signaling in AI-resistant breast cancer. Down-regulation of PDCD4 is associated with AI resistance and a poor prognosis in patients with ER-positive breast cancer.
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Proteínas Reguladoras de la Apoptosis/genética , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ARN/genética , Receptores de Estrógenos/metabolismo , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Regulación hacia Abajo , Femenino , Humanos , Estimación de Kaplan-Meier , MicroARNs/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant clinical problem for a considerable number of patients. The oncogenic transcription factor c-MYC (hereafter referred to as MYC), which regulates glutamine metabolism in cancer cells, has been linked to endocrine resistance. We were interested in whether MYC-mediated glutamine metabolism is also associated with aromatase inhibitor (AI) resistant breast cancer. We studied the expression and regulation of MYC and the effects of inhibition of MYC expression in both AI sensitive and resistant breast cancer cells. Considering the role of MYC in glutamine metabolism, we evaluated the contribution of glutamine to the proliferation of AI sensitive and resistant cells, and performed RNA-sequencing to investigate mechanisms of MYC-mediated glutamine utilization in AI resistance. We found that glutamine metabolism was independent of estrogen but still required estrogen receptor (ER) in AI resistant breast cancer cells. The expression of MYC oncogene was up-regulated through the cross-talk between ER and human epidermal growth factor receptor 2 (HER2) in AI resistant breast cancer cells. Moreover, the glutamine transporter solute carrier family (SLC) 1A5 was significantly up-regulated in AI resistant breast cancer cells. ER down-regulator fulvestrant inhibited MYC, SLC1A5, glutaminase (GLS) and glutamine consumption in AI resistant breast cancer cells. Inhibition of MYC, SLC1A5 and GLS decreased AI resistant breast cancer cell proliferation. Our study has uncovered that MYC expression is up-regulated by the cross-talk between ER and HER2 in AI resistant breast cancer cells. MYC-mediated glutamine metabolism is associated with AI resistance of breast cancer.
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Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Glutamina/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptor ErbB-2/metabolismo , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Estradiol/análogos & derivados , Estradiol/farmacología , Femenino , Fulvestrant , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-myc/genéticaRESUMEN
OBJECTIVES: Aromatase deficiency is a rare disorder resulting in estrogen insufficiency in humans. It has been reported in remarkably few men with loss-of-function mutations in the CYP19A1 gene encoding the aromatase, a cytochrome P450 enzyme that plays a crucial role in the biosynthesis of estrogens from androgens. We investigated a non-consanguineous family including an adult man with clinical features of aromatase deficiency, and studied the effects of estrogen replacement in the man. METHODS: We investigated the clinical and biochemical phenotype, performed CYP19A1 mutational analysis in the family and 50 unrelated persons, studied the effects of CYP19A1 mutations on aromatase protein structure, functionally characterized the mutations by cell-based aromatase activity assays, and studied the effects of estrogen replacement on the bone, lipid, liver and glucose metabolism. RESULTS: The man with clinical features of aromatase deficiency had novel compound heterozygous CYP19A1 mutations (Y81C and L451P) that were not found in 50 unrelated persons. Three-dimensional modeling predicted that Y81C and L451P mutants disrupted protein structure. Functional studies on the basis of in vitro expression showed that Y81C and L45P mutants significantly decreased the aromatase activity and catalytic efficiency. Estrogen replacement in the man increased bone mineral density, accelerated bone maturation, improved lipid profile and liver steatosis, and improved glucose levels but not insulin resistance. CONCLUSIONS: We have identified two novel CYP19A1 missense mutations in an aromatase-deficient man. Estrogen replacement in the man shows great impact on recovering the impairments in the bone, lipid, liver and glucose metabolism, but fails to improve insulin resistance.
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Trastornos del Desarrollo Sexual 46, XX , Aromatasa/deficiencia , Densidad Ósea , Terapia de Reemplazo de Estrógeno , Estrógenos/uso terapéutico , Glucosa/metabolismo , Ginecomastia , Infertilidad Masculina , Metabolismo de los Lípidos , Hígado/metabolismo , Errores Innatos del Metabolismo , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/metabolismo , Trastornos del Desarrollo Sexual 46, XX/patología , Adulto , Sustitución de Aminoácidos , Animales , Aromatasa/genética , Aromatasa/metabolismo , Densidad Ósea/efectos de los fármacos , Densidad Ósea/genética , Huesos/metabolismo , Células CHO , Cricetulus , Glucosa/genética , Ginecomastia/tratamiento farmacológico , Ginecomastia/genética , Ginecomastia/metabolismo , Ginecomastia/patología , Humanos , Infertilidad Masculina/tratamiento farmacológico , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Hígado/patología , Masculino , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , Modelos Moleculares , Mutación Missense , Estructura Terciaria de ProteínaRESUMEN
Nutrient elements and salinity in soil covered by different vegetations including Phragmites australis (Clay.) Trin., Typha orientalis Presl., Puccinellia distans Parl, and Suaeda salsa in Shuangtaizi estuarine wetlands were investigated to study their distribution characteristics and to reveal the nutrient element variation during the vegetation succession processes. Results indicated that total potassium, total phosphorus and salinity were different significantly in soil between different plant communities while available phosphorus, total nitrogen, available nitrogen, available potassium, total sulfur, iron and soil organic carbon were different insignificantly. Correlation analysis suggested that soil organic carbon were related significantly to total nitrogen, available phosphorus, available potassium, which implied that decomposition of plant litter might be the mail source of soil nitrogen and available nutrient. Salinity was significantly related to total phosphorus and iron in soil. In Shuangtaizi estuarine wetland soil, ratios of carbon to nitrogen (R(C/N)) was in the range of 12.21-26.33 and the average value was 18.21, which was higher than 12.0. It indicated that soil organic carbon in Shuangtaizi estuarine mainly came from land but not ocean and plants contributed the most of soil organic matters. There was no significant difference in R(C/N) between soil from the four plant communities (F = 1.890, p = 0.151). R(C/N) was related significantly to sol salinity (r = 0.346 3, p = 0.035 8) and was increasing with soil salinity.
Asunto(s)
Desarrollo de la Planta , Salinidad , Suelo/análisis , Humedales , Carbono/análisis , Chenopodiaceae/crecimiento & desarrollo , China , Nitrógeno/análisis , Poaceae/crecimiento & desarrollo , Ríos , Typhaceae/crecimiento & desarrolloRESUMEN
Type 2 diabetes mellitus (T2DM) results from insulin resistance and ß-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic α cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if α-cell numbers increase in T2DM and what factor (s) regulate α-cell turnover. Lepr(db)/Lepr(db) (db/db) mice were used as a T2DM model and αTC1 cells were used to study potential α-cell trophic factors. Here, we demonstrate that in db/db mice α-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of α cells significantly increased α-cell proliferation in a concentration-dependent manner compared to non-insulin-treated α cells. Insulin up-regulated α-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in αTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened α-cell proliferation, and increased intra-islet insulin content in ß cells in db/db mice. These studies illustrate that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting α cells and glucagon.