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BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension with a low incidence. Despite pulmonary endarterectomy(PEA) being the preferred treatment for CTEPH, for patients who failed medical therapy and who are not suitable candidates for PEA, lung transplantation (LT) is still the only effective treatment for end-stage CTEPH; however, there are currently very few reports on the efficacy of LT for CTEPH. METHODS: We retrospectively analyzed the clinical data of seven patients diagnosed with CTEPH between July 2019 and July 2021. The follow-up deadline was March, 2022. RESULTS: The mean age at admission was 54 ± 12 years. The average value of mean pulmonary artery pressure (mPAP) was 40 ± 5 mmHg. The mean preoperative oxygenation index(PaO2/FiO2) was 203 ± 56 mm Hg. After evaluation, one patient underwent left LT and the rest underwent bilateral LT. Three patients received intraoperative veno-venous extracorporeal membrane oxygenation (ECMO) support, and four patients received intraoperative veno-arterial ECMO support. The average postoperative mPAP was 19 ± 4 mmHg. The mean postoperative oxygenation index(PaO2/FiO2) was 388 ± 83 mmHg. There was a significant difference between the preoperative and postoperative mPAP and oxygenation index(PaO2/FiO2). All patients recovered well and were discharged 37 ± 19 days postoperatively. The mean follow-up duration was 19 ± 8 months. There was no recurrence of CTEPH. CONCLUSIONS: LT is an effective treatment for end-stage CTEPH, which can improve cardiopulmonary function and quality of life and prolong survival. Patients who are unable to tolerate PEA should be considered for LT as early as possible when internal medicine failed.
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Hipertensión Pulmonar , Trasplante de Pulmón , Embolia Pulmonar , Humanos , Persona de Mediana Edad , Femenino , Masculino , Estudios Retrospectivos , Hipertensión Pulmonar/cirugía , Embolia Pulmonar/cirugía , Embolia Pulmonar/complicaciones , Adulto , Enfermedad Crónica , Resultado del Tratamiento , Oxigenación por Membrana Extracorpórea/métodos , Anciano , Endarterectomía/métodosRESUMEN
Oncolytic viruses (OVs) represent an emerging immunotherapeutic strategy owing to their capacity for direct tumor lysis and induction of antitumor immunity. However, hurdles like transient persistence and moderate efficacy necessitate innovative approaches. Metabolic remodeling has recently gained prominence as a strategic intervention, wherein OVs or combination regimens could reprogram tumor and immune cell metabolism to enhance viral replication and oncolysis. In this review, we summarize recent advances in strategic reprogramming of tumor and immune cell metabolism to enhance OV-based immunotherapies. Specific tactics include engineering viruses to target glycolytic, glutaminolytic, and nucleotide synthesis pathways in cancer cells, boosting viral replication and tumor cell death. Additionally, rewiring T cell and NK cell metabolism of lipids, amino acids, and carbohydrates shows promise to enhance antitumor effects. Further insights are discussed to pave the way for the clinical implementation of metabolically enhanced oncolytic platforms, including balancing metabolic modulation to limit antiviral responses while promoting viral persistence and tumor clearance.
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Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Viroterapia Oncolítica/métodos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/metabolismo , Virus Oncolíticos/metabolismo , Animales , Replicación Viral , Inmunoterapia/métodos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismoRESUMEN
Background: Curcumin (CUR), an effective traditional Chinese medicinal extract, displays good anti-cancer activity against various cancers. Nevertheless, the impacts and fundamental mechanisms of CUR to treat esophageal squamous cell carcinoma (ESCC) yet to be comprehensively clarified. This study examined the suppressive impacts of CUR on ESCC. Methods: For a comprehensive understanding of the effect of CUR in ESCC. The CUR targets and ESCC-related genes were identified respectively, and the intersection targets between CUR and ESCC were acquired. Then, we examined the intersection targets and discovered genes that were expressed differently in ESCC. Using DAVID, enrichment analyses were conducted on the targets of CUR-ESCC. The STRING database and Cytoscape v.3.9.1 were utilized to build networks for protein-protein interaction (PPI) and drug-target-pathway. Furthermore, the interactions between CUR and its core targets were confirmed by molecular docking studies. To confirm the effects of CUR on ESCC cells, in vitro experiments were finally conducted. Results: Overall, 47 potential CUR targets for ESCC treatment were identified. The KEGG pathway enrichment analysis identified 61 signaling pathways, primarily associated with the FoxO signaling, the cell cycle, cellular senescence, the IL-17 signaling pathway which play important roles in ESCC progression. In the PPI network and the docking results identified CHEK1 and CDK6 as the core targets that positively associated with ESCC survival. CUR arrested ESCC cells at the G2/M and S phases, as shown by flow cytometry. Colony formation and CCK8 assays showed that CUR can inhibit the proliferative ability of ESCC cells. The Transwell invasion results validated that CUR can significantly inhibit the invasion rates of ESCC cells. Conclusion: Collectively, these findings indicate that CUR exhibits pharmacological effects on multiple targets and pathways in ESCC.
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Head and neck squamous cell carcinoma (HNSCC) is a formidable cancer type that poses significant treatment challenges, including radiotherapy (RT) resistance. The metabolic characteristics of tumors present substantial obstacles to cancer therapy, and the relationship between RT and tumor metabolism in HNSCC remains elusive. Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Here, we report that after RT, glutamine levels rise in HNSCC, and the glutamine transporter protein SLC1A5 is upregulated. Notably, blocking glutamine significantly enhances the therapeutic efficacy of RT in HNSCC. Furthermore, inhibition of glutamine combined with RT triggers immunogenic tumor ferroptosis, a form of nonapoptotic regulated cell death. Mechanistically, RT increases interferon regulatory factor (IRF) 1 expression by activating the interferon signaling pathway, and glutamine blockade augments this efficacy. IRF1 drives transferrin receptor expression, elevating intracellular Fe2+ concentration, disrupting iron homeostasis, and inducing cancer cell ferroptosis. Importantly, the combination treatment-induced ferroptosis is dependent on IRF1 expression. Additionally, blocking glutamine combined with RT boosts CD47 expression and hinders macrophage phagocytosis, attenuating the treatment effect. Dual-blocking glutamine and CD47 promote tumor remission and enhance RT-induced ferroptosis, thereby ameliorating the tumor microenvironment. Our work provides valuable insights into the metabolic and immunological mechanisms underlying RT-induced ferroptosis, highlighting a promising strategy to augment RT efficacy in HNSCC.
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Ferroptosis , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Glutamina/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Antígeno CD47 , Línea Celular Tumoral , Hierro/metabolismo , Microambiente Tumoral , Antígenos de Histocompatibilidad Menor/metabolismo , Sistema de Transporte de Aminoácidos ASC/metabolismoRESUMEN
AIM OF THE STUDY: Exploring the protective effect of ARC@DPBNP on lipopolysaccharides (LPS)-induced ALI and its underlying mechanism. MATERIALS AND METHODS: ALI model was established by intransally administrating LPS (4 mg/kg) into C57BL/6 mice. The suppression effects of ALI was first compared between ARC (intragastric administrated, with doses ranging from 10 to 80 mg/kg) and ARC@BPBNPs (intratracheally administrated, with doses ranging from 1 to 4 mg/kg). Changes in lung histology post intratracheal intervention of 3 mg/kg ARC@DPBNPs were detected. The expression of pyrotosis pathway-related proteins in lungs as well as in RAW264.7 cells was detected by western blotting. The ASC expression in lung macrophages was examined using immune-fluorescent staining. The polarization of RAW264.7 cells and lung macrophages were detected by flow cytometry. The network pharmacology was constructed by Cytoscape, and the molecular docking was perfomed by AutoDock Vina. RESULTS: Docking predicted the high affinity of ARC to MAPK1 (ERK2). HE staining showed that ARC@DPBNPs attenuated LPS-induced ALI at a remarkably lower dose than ARC. The improved histopathological changes, lung W/D weight ratio, and decreased of inflammatory factor levels in lung collectively demonstrated the alleviation effects of ARC@DPBNPs. Compared with the LPS group, ARC@DPBNPs down-regulated the ERK pathway, resulted in a suppression of the macrophage pyroptosis and M1 polarization. This suppression effects could be removed by the ERK activator Ro 67-7476. CONCLUSION: ARC@DPBNPs attenuated ALI by suppressing LPS-induced macrophage pyroptosis and polarization, probably through down-regulation of the ERK pathway.
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Lesión Pulmonar Aguda , Sistema de Señalización de MAP Quinasas , Animales , Ratones , Lipopolisacáridos/farmacología , Piroptosis , Simulación del Acoplamiento Molecular , Ratones Endogámicos C57BL , Macrófagos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Pulmón/patologíaRESUMEN
Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8+ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.
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Neoplasias , Linfocitos T , Humanos , Epigenoma , Linfocitos Infiltrantes de Tumor , Inmunoterapia , Neoplasias/genética , Neoplasias/terapiaRESUMEN
BACKGROUND: Primary graft dysfunction, which is directly related to cold ischemia-reperfusion (CI/R) injury, is a major obstacle in lung transplantation (LTx). Ferroptosis, a novel mode of cell death elicited by iron-dependent lipid peroxidation, has been implicated in ischemic events. This study aimed to investigate the role of ferroptosis in LTx-CI/R injury and the effectiveness of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, in alleviating LTx-CI/R injury. METHODS: LTx-CI/R-induced signal pathway alterations, tissue injury, cell death, inflammatory responses, and ferroptotic features were examined in human lung biopsies, the human bronchial epithelial (BEAS-2B) cells, and the mouse LTx-CI/R model (24-h CI/4-h R). The therapeutic efficacy of Lip-1 was explored and validated both in vitro and in vivo. RESULTS: In human lung tissues, LTx-CI/R activated ferroptosis-related signaling pathway, increased the tissue iron content and lipid peroxidation accumulation, and altered key protein (GPX4, COX2, Nrf2, and SLC7A11) expression and mitochondrial morphology. In BEAS-2B cells, the hallmarks of ferroptosis were significantly evidenced at the setting of both CI and CI/R compared with the control, and the effect of adding Lip-1 only during CI was much better than that of only during reperfusion by Cell Counting Kit-8. Furthermore, Lip-1 administration during CI markedly relieved LTx-CI/R injury in mice, as indicated by significant improvement in lung pathological changes, pulmonary function, inflammation, and ferroptosis. CONCLUSIONS: This study revealed the existence of ferroptosis in the pathophysiology of LTx-CI/R injury. Using Lip-1 to inhibit ferroptosis during CI could ameliorate LTx-CI/R injury, suggesting that Lip-1 administration might be proposed as a new strategy for organ preservation.
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Ferroptosis , Trasplante de Pulmón , Daño por Reperfusión , Humanos , Animales , Ratones , Daño por Reperfusión/etiología , Daño por Reperfusión/prevención & control , Trasplante de Pulmón/efectos adversos , Modelos Animales de Enfermedad , HierroRESUMEN
BACKGROUND: Chronic kidney disease (CKD) is a progressive and irreversible complication in lung transplant patients who have received long-term treatment with tacrolimus. This study aimed to verify long-term tacrolimus exposure values in CKD progression. METHODS: We retrospectively analyzed the clinical data of adult lung transplant recipients performed at our center between 2012 and October 2015. Patients who completed the 5-year follow-up period were enrolled in this study. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. RESULTS: Eighty patients were analyzed. Compared with baseline (109 ± 38.1 mL/min/1.73 m2), the average eGFR values of our patients gradually decreased during the fifth-year post transplantation (46.5%, 58.3 ± 28.3 mL/min/1.73 m2), and the decline in eGFR values was particularly pronounced in the first year (31.2%, 74.6 ± 28.91 mL/min/1.73 m2). Moreover, 10 (12.7%), 21 (26.9%), 24 (31.2%), 28 (41.2%), and 48 (60%) patients had eGFR <60 mL/min/1.73 m2 at 3, 6, 1, 3, and 5 years after lung transplantation (LT), respectively. A significant negative correlation was found between tacrolimus dose and eGFR 6 months after LT (P = 0.0414). We found no correlation between the serum tacrolimus concentration and CKD progression. CONCLUSION: eGFR constantly decreased and the incidence of CKD increased during the 5-year follow-up period after LT. The tacrolimus dose had a significant negative correlation with eGFR at 6 months after LT. Meanwhile, whole-blood tacrolimus trough concentrations were not correlated with eGFR decline. When possible, lower dosing within 1 year after LT can reduce potential nephrotoxic side effects.
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Trasplante de Hígado , Trasplante de Pulmón , Insuficiencia Renal Crónica , Adulto , Humanos , Tacrolimus/uso terapéutico , Tacrolimus/efectos adversos , Estudios Retrospectivos , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Trasplante de Hígado/efectos adversos , Tasa de Filtración GlomerularRESUMEN
Background: Idiopathic pulmonary fibrosis is a severe and deadly form of diffuse parenchymal lung disease and treatment options are few. Alveolar epithelial type 2 (AEC2) cell senescence is implicated in the pathogenies of IPF. A major bioactive compound from the traditional Chinese medicine Fructus arctii, arctiin (ARC) has robust anti-inflammatory, anti-senescence, and anti-fibrosis functions. However, the potential therapeutic effects of ARC on IPF and the underlying mechanisms involved are still unknown. Methods: First of all, ARC was identified as an active ingredient by network pharmacology analysis and enrichment analysis of F. arctii in treating IPF. We developed ARC-encapsulated DSPE-PEG bubble-like nanoparticles (ARC@DPBNPs) to increase ARC hydrophilicity and achieve high pulmonary delivery efficiency. C57BL/6 mice were used to establish a bleomycin (BLM)-induced pulmonary fibrosis model for assessing the treatment effect of ARC@DPBNPs on lung fibrosis and the anti-senescence properties of AEC2. Meanwhile, p38/p53 signaling in AEC2 was detected in IPF lungs, BLM-induced mice, and an A549 senescence model. The effects of ARC@DPBNPs on p38/p53/p21 were assessed in vivo and in vitro. Results: Pulmonary route of administration of ARC@DPBNPs protected mice against BLM-induced pulmonary fibrosis without causing significant damage to the heart, liver, spleen, or kidney. ARC@DPBNPs blocked BLM-induced AEC2 senescence in vivo and in vitro. The p38/p53/p21 signaling axis was significantly activated in the lung tissues of patients with IPF, senescent AEC2, and BLM-induced lung fibrosis. ARC@DPBNPs attenuated AEC2 senescence and pulmonary fibrosis by inhibiting the p38/p53/p21 pathway. Conclusion: Our data suggest that the p38/p53/p21 signaling axis plays a pivotal role in AEC2 senescence in pulmonary fibrosis. The p38/p53/p21 signaling axis inhibition by ARC@DPBNPs provides an innovative approach to treating pulmonary fibrosis in clinical settings.
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Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells associated with favourable prognosis and response to immunotherapy in cancer, but the immune architecture of TLSs remains poorly elucidated. Here, we hypothesize that the spatial architecture of leukocytes in TLSs can be reconstructed de novo, at least partially, by cell-inherent chemokine receptors profiles. Single-cell RNA-sequencing (scRNA-seq) revealed 47 subpopulations of leukocytes in head and neck squamous cell carcinoma (HNSC). Combined with bulk RNA-seq, we observed that CXCR3, CCR7, CCR6, CXCR5, and CCR1 are TLS-associated chemokine receptors. According to the spatial reference, the cellular atlas with TLS-associated chemokine receptors in HNSC TLSs was elaborately portrayed by multiplex immunohistochemistry (mIHC). Subsequently, we explored the functions and evolutionary trajectory of cells distributed in TLSs. Our investigation presents an approach to reconstructing the immune architecture of TLSs, which would help boost the antitumor immune response by inducing neogenesis TLSs in HNSC.
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Neoplasias de Cabeza y Cuello , Estructuras Linfoides Terciarias , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Estructuras Linfoides Terciarias/patología , Pronóstico , Receptores de QuimiocinaRESUMEN
BACKGROUND: CD8+ T cells play a critical role in the innate antitumour immune response. Recently, CD8+ T cell dysfunction has been verified in various malignant cancers, including non-small cell lung cancer (NSCLC). However, the molecular biological mechanisms of CD8+ T cell dysfunction in human NSCLC are still unclear. METHODS: The expression of circular ubiquitin-specific protease-7 (circUSP7) in NSCLC tissues, exosomes, and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Exosomes were isolated from the culture medium of NSCLC cells and the plasma of NSCLC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit. The exosomes were then characterized by transmission electronic microscopy (TEM), NanoSight and western blotting. The role of circUSP7 in CD8+ T cell dysfunction was assessed by enzyme-linked immunosorbent assay (ELISA). In vivo circular RNA (circRNA) precipitation (circRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were performed to explore the molecular mechanisms of circUSP7 in CD8+ T cells. In a retrospective study, the clinical characteristics and prognostic significance of circUSP7 in NSCLC tissues were determined. RESULTS: The expression levels of circUSP7 were higher in human NSCLC tissues than in matched adjacent nontumour tissues. Increased levels of circUSP7 indicate poor clinical prognosis and CD8+ T cell dysfunction in patients with NSCLC. The circUSP7 found in NSCLC patient plasma is predominantly secreted by NSCLC cells in an exosomal manner, and circUSP7 inhibits IFN-γ, TNF-α, Granzyme-B and Perforin secretion by CD8+ T cells. Furthermore, circUSP7 inhibits CD8+ T cell function by upregulating the expression of Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) via sponging miR-934. Finally, we show that circUSP7 may promote resistance to anti-PD1 immunotherapy in NSCLC patients. CONCLUSIONS: Exosomal circUSP7 is predominantly secreted by NSCLC cells and contributes to immunosuppression by promoting CD8+ T cell dysfunction in NSCLC. CircUSP7 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for NSCLC patients.
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Linfocitos T CD8-positivos/metabolismo , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , ARN Circular/genética , Peptidasa Específica de Ubiquitina 7/genética , Adulto , Anciano , Animales , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Exosomas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Recuento de Linfocitos , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Interferencia de ARNRESUMEN
Thymoma is the most common tumor of the anterior mediastinum. Routine imaging methods such as computed tomography or magnetic resonance imaging often lead to misdiagnosis between thymoma and other thymic abnormalities. Therefore, urgently needed is to develop a new diagnostic strategy. Here we identify interleukin-8 (IL-8) as a biomarker for auxiliary diagnosis of thymoma. We find that IL-8 levels in naïve T cells are markedly elevated in patients with thymoma compared to those with other thymic tumors. IL-8 levels in naive T cells are significantly decreased after surgical resection in thymoma patients, and rise again when thymoma recurs. A receiver operating characteristic curve analysis shows that IL-8 evaluation performs well in thymoma identification, with high specificities and sensitivities. We also observe significant clinical relevance between IL-8 levels in naïve T cells and clinicopathological features. In conclusion, our study suggests that IL-8 is a biomarker for thymoma identification and recurrence surveillance.
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Interleucina-8/sangre , Recurrencia Local de Neoplasia/sangre , Timoma/sangre , Neoplasias del Timo/sangre , Adulto , Anciano , Biomarcadores de Tumor/sangre , Femenino , Humanos , Interleucina-8/genética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Timoma/genética , Timoma/patología , Neoplasias del Timo/genética , Neoplasias del Timo/patología , Adulto JovenRESUMEN
BACKGROUND: Children aged 6-7 years are in the early mixed dentition, which is a period of high prevalence of dental caries and other dental diseases and a critical period for the formation of oral health behaviors. Therefore, good oral hygiene habits of children and oral health knowledge of parents are very important. This study sought to explore the relationship between children's oral health behaviors, parental oral health knowledge, parental choices of pit and fissure sealants, and parents' education levels based on a large-scale sample size for the first time, and to compare the influences of parental education levels between parents. METHODS: Families of the first and second graders of primary schools in Wuhan Hongshan District were included in this study. A total of 8446 questionnaires were collected to obtain comprehensive information on children's oral health behaviors, parents' oral health knowledge and parents' pit and fissure sealants-related choices. The relationship between these outcome variables and parents' education levels were studied using logistic regression analysis and chi-square test. RESULTS: Parents who reported good educational background had more favorable oral health knowledge than those of other parents, and their children had better oral hygiene behaviors. Four indicators of five measures to children's oral health behaviors were significantly associated with mother's education level (P < 0.05), and three of them were related to father's education level (P ≤ 0.01). Moreover, seven indicators of eight measures to parents' oral health knowledge were significantly related to mother's education level (P < 0.05) and four of them were affected by the father's (P < 0.05). In addition, parents with higher educational attainments paid more attention to the completeness of medical facilities, the environment of dental practice, the distance to treatment sites, and took less concern of children's willingness when choosing the pit and fissure sealants sites. CONCLUSIONS: In families with children at the early mixed dentition stage, parents with higher education levels tend to have better oral health knowledge and more oral health care needs, such as pit and fissure sealants. In addition, children of parents who have better educated parents tend to perform better oral hygiene practices.
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Caries Dental/prevención & control , Escolaridad , Conductas Relacionadas con la Salud , Conocimientos, Actitudes y Práctica en Salud , Salud Bucal , Padres/psicología , Selladores de Fosas y Fisuras , Adulto , Niño , Femenino , Educación en Salud Dental , Alfabetización en Salud , Humanos , Masculino , Higiene Bucal/psicología , Encuestas y Cuestionarios , Cepillado DentalRESUMEN
Objectives: An increase in the trimethylation of lysine 4 of histone 3 (H3K4me3) has been reported to be involved in the development of several types of tumors. However, the level and role of H3K4me3 in human esophageal cancer (HEC) remain unknown. Here, we assessed the role and clinical significance of H3K4me3 in HEC. Methods: The level of H3K4me3 was determined in 15 pairs of HEC and paracancerous tissues by Western blotting. A tissue microarray including samples from 100 HEC patients was analyzed by immunohistochemistry to determine the relationship between the level of H3K4me3 and the clinicopathological features of HEC patients. Then, the levels of H3K4me3 in HEC cells were elevated via knockdown of inhibitor of growth family member 4(Ing4) expression. Finally, the prognostic significance of H3K4me3 levels in HEC patients was further analyzed. Results: We found that H3K4me3 levels were frequently elevated in HEC tissues compared with adjacent esophageal tissues, and elevated H3K4me3 was significantly associated with poor tumor differentiation (p =1.39×10-5) and advanced tumor stage (p=8.5×10-5). After Ing4 knockdown in HEC cells, we found that the cell proliferation, metastasis, invasion and colony formation abilities were enhanced compared to those in the control cells. Notably, we found that HEC patients with a high level of H3K4me3 exhibited an unfavorable 5-year survival rate compared to those with a low level of H3K4me3 (p=6.8×10-5). The univariate analysis showed that the tumor differentiation, TNM stage, and H3K4me3 level were predictors of the overall survival rate of HEC patients. In the multivariate analysis, tumor stage (p=0.015) and H3K4me3 level (p=0.034) were revealed to be independent parameters for predicting the prognosis of HEC patients. Conclusions: Thus, high levels of H3K4me3 may be used as a meaningful biomarker for HEC prognosis evaluation.
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BACKGROUNDS: Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function of lncRNA PSMA3-AS1 in ESCC is unclear. Therefore, we aimed to explore the functions and potential mechanisms of PSMA3-AS1 in ESCC cells progression. RESULTS: Here, we found that PSMA3-AS1 expression was significantly up-regulated in ESCC tissues. Forced PSMA3-AS1 expression was correlated with tumor size, distant metastasis, and poor prognosis in ESCC patients. Functionally, PSMA3-AS1-overexpression promoted ESCC cells proliferation, invasion, and migration in vitro. Mechanistically, PSMA3-AS1 up-regulated EZH2 expression by competitively binding to miR-101. CONCLUSION: PSMA3-AS1 is significantly up-regulated in ESCC tissues, and the PSMA3-AS1/miR-101/EZH2 axis plays a critical role in ESCC progression. Taken together, our results may provide promising targets for ESCC therapy. METHODS: PSMA3-AS1 and miR-101 expression were explored using qRT-PCR in ESCC tissues and cell lines. Immunohistochemistry assays were carried out to analyze EZH2 (enhancer of zeste homolog) protein expression. RIP, dual-luciferase reporter, fluorescence in situ hybridization, and biotin pull-down assays were used to detect the interactions of PSMA3-AS1, miR-101 and EZH2. The biological functions of PSMA3-AS1 in PSMA3-AS1-altered cells were explored using CCK-8, colony formation, wound healing, and transwell assays in vitro.
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Proteína Potenciadora del Homólogo Zeste 2/genética , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Interferencia de ARN , ARN Largo no Codificante/genética , Regiones no Traducidas 3' , Adulto , Anciano , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Complejo de la Endopetidasa Proteasomal/genéticaRESUMEN
The dysregulation of circular RNA (circRNA) expression is involved in the progression of several cancers, including non-small cell lung cancer (NSCLC). However, the role and underlying molecular mechanisms of circRNA FGFR3 (circFGFR3) in NSCLC progression remains unknown. Here, we used quantitative real-time polymerase chain reaction to validate that circFGFR3 expression was higher in NSCLC tissues than in the paratumor tissues. Furthermore, our study indicated that the forced circFGFR3 expression promoted NSCLC cell invasion and proliferation. Mechanistically, we found that circFGFR3 promoted NSCLC cell invasion and proliferation via competitively combining with miR-22-3p to facilitate the galectin-1 (Gal-1), p-AKT, and p-ERK1/2 expressions. Clinically, we revealed that the high circFGFR3 expression correlates with the poor clinical outcomes in patients with NSCLC. Together, these data provide mechanistic insights into the circFGFR3-mediated regulation of both the AKT and ERK1/2 signaling pathways by sponging miR-22-3p and increasing Gal-1 expression.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , MicroARNs/genética , ARN Circular/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Células A549 , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Galectina 1/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Persona de Mediana Edad , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Invasividad Neoplásica/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Resultado del TratamientoRESUMEN
Recent evidence indicated ubiquitin like with PHD and ring finger domains 2 (UHRF2) was involved in various human diseases, especially in cancer, however, its roles in cancer are still in dispute. Here, we found UHRF2 expression was decreased in lung cancer tissues compared with adjacent normal tissues by referring to the Oncomine Database, which was further identified by immunoblotting and quantitative real-time polymerase chain reaction assays. Secondly, we found knockdown of UHRF2 in A549 and 95-D cell lines enhanced the capability of proliferation, invasion and migration, while forced UHRF2 expression inhibited NSCLC cells proliferation,invasion and migration. Mechanistically, dot-blot and western blot assays indicated that the level of UHRF2 was positively correlated with 5-hmC level by affecting ten-eleven translocation 2 (TET2) expression. Clinically, UHRF2 downregulation is significantly correlated with a malignant phenotype, including larger tumor size and poor differentiation. Moreover, UHRF2 downregulated correlates with shorter overall survival(OS). Conclusion: Our findings indicate that UHRF2 is a tumor suppressor in NSCLC by influence TET2 expression and serve as a potential therapeutic target in NSCLC.
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Aberrant expression of TRIM-containing protein 44 (TRIM44) acts as a promoter in multiple cancers. Here, we investigated the biological functions and clinical significance of TRIM44 in human esophageal cancer (HEC). TRIM44 expression was significantly higher in HEC tissues than corresponding normal tissues at both the mRNA (2.42 ± 0.52 vs 0.99 ± 0.25) and protein (1.01 ± 0.27 vs 0.30 ± 0.13) levels. Patients with high TRIM44 expression showed poor differentiation (P = 1.39 × 10-5 ), advanced TNM stage (P = 3.87 × 10-4 ) and, most importantly, significantly poorer prognosis (P = 2.80 × 10-5 ). TRIM44 played a crucial role in epithelial mesenchymal transition (EMT). A significant correlation was observed between TRIM44 and Ki67 expression. We demonstrated that TRIM44 markedly enhanced HEC cell proliferation, migration, and invasion. Additionally, TRIM44 was involved in the AKT/mTOR signaling pathway and its downstream targets, such as STAT3 phosphorylation. Thus, elevated TRIM44 expression promotes HEC development by EMT via the AKT/mTOR pathway, and TRIM44 may be a novel prognostic indicator for HEC patients after curative resection.
Asunto(s)
Proteínas Portadoras/metabolismo , Transición Epitelial-Mesenquimal , Neoplasias Esofágicas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Anciano , Proteínas Portadoras/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Esofagectomía , Esófago/patología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular , Estimación de Kaplan-Meier , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fosforilación , Pronóstico , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteínas de Motivos TripartitosRESUMEN
Fused in sarcoma/translocated in liposarcoma (FUS/TLS), a ubiquitous and multifunctional DNA and RNA-binding protein, contributes an important function in cancer and neurodegenerative disease; however, its role in lung cancer remains unclear. In the present study, the expression of FUS/TLS in non-small cell lung cancer (NSCLC) and the significance of FUS/TLS for predicting the clinical outcome of patients with NSCLC, was examined. FUS/TLS expression was investigated in NSCLC tissues and their matched adjacent non-tumorous tissues by reverse transcription-quantitative polymerase chain reaction, western blotting, and immunohistochemistry. Tissue microarrays representing 208 patients with NSCLC were used to determine the expression pattern and associations with FUS/TLS using immunohistochemistry. Prognostic significance was assessed by Kaplan-Meier survival estimates and log-rank tests. Data revealed that FUS/TLS expression was elevated in NSCLC tissues compared with corresponding normal tissue mRNA (9.27±0.73 vs. 6.15±0.60) and protein (3.32±0.75 vs. 0.30±0.07) levels. In tissue microarrays, FUS/TLS was highly expressed in 103 (49.5%, 103/208) NSCLC tissues compared with adjacent normal lung tissues (28.4%, 59/208). Overexpression of FUS/TLS was associated with higher tumor node metastasis stage (P=0.016), poorer differentiation (P=0.008), large tumor size (P=0.019) and predicted poor prognosis (P=0.005) in patients with NSCLC. Notably, correlation analysis revealed a significant inverse association between the expression of FUS/TLS and E-cadherin (r2=0.51; P=0.036). Furthermore, patients with NSCLC with high FUS/TLS and impaired E-cadherin expression had a notably poor prognosis (P=4.01×10-4). Thus, the results from the present study indicate that elevated FUS/TLS expression promotes NSCLC progression. FUS/TLS, alone or in combination with E-cadherin, is a novel prognostic predictor for patients with NSCLC.
RESUMEN
Objectives: Ring finger protein 38 (RNF38), as an E3 ubiquitin ligase, plays an essential role in multiple biological processes by controlling cell apoptosis, cell cycle and DNA repair, and resides in chromosome 9 (9p13) which is involvement in cancer pathogenesis including lung cancer. However, its function in tumorigenesis remains unclear. Hence, this study set out to investigate the biological function and clinical implications of RNF38 in non-small cell lung cancer (NSCLC). Materials and Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect RNF38 protein and mRNA levels in NSCLC and corresponding paratumor tissues. Tissue microarrays (TMA) analysis of 208 NSCLC cases were used to evaluate the relationship between RNF38 expression and clinical implications. Prognostic value was assessed by Kaplan-Meier analysis and log-rank tests. Wound-healing assays, trans-well assays, colony formation assays and CCK8 were used to assess cell migration, invasion and proliferative ability respectively. The analysis of epithelial-to-mesenchymal transition (EMT) phenotype was carried out by immunofluorescence and western blot. Results: Our data revealed that elevated RNF38 expression were more common in NSCLC tissues than paired normal tissues in both mRNA (2.82 ± 0.29 vs. 1.23 ± 0.13) and protein (2.75 ± 0.09 vs. 1.24 ± 0.02) level. High levels of RNF38 expression were significantly associated with lymph node metastases, higher TNM stages (p=0.011), larger tumor size (p=2.09E-04) and predicted poor prognosis. RNF38 expression was inversely correlated with E-cadherin expression (P= 0.025). Moreover, downregulation of RNF38 impaired the proliferation, metastatic and invasive abilities in NSCLC cells. In addition, aberrant RNF38 expression could modulate the key molecules of EMT. Conclusions: Our results indicate that elevated expression of RNF38 is significantly associated with the proliferation and metastatic capacity of NSCLC cells, and RNF38 overexpression can serve as a biomarker of NSCLC poor prognosis.