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Thymoma is closely associated with myasthenia gravis (MG). However, due to the heterogeneity of thymoma and the intricate pathogenesis of MG, it remains unclear why some patients with thymoma develop MG and others do not. In this study, we conducted a comparative phenotype analysis of thymocytes in type B thymomas in patients with MG (MG (+) thymomas) and without MG (MG (-) thymomas) via fluorescence-activated cell sorting (FACS). Our results show that the developmental stages defined by the expression of CD3, CD4, and CD8 were largely maintained in both MG (+) and MG (-) thymomas, with CD4+CD8+ cells constituting the majority of thymocytes in type B thymoma, and no significant difference between this cell population was observed in MG (+) and MG (-) thymomas.We discovered that CD4+CD8+ thymocytes in MG (+) thymomas expressed low levels of αß TCR and high levels of IL-7 receptor α (IL-7Rα), whereas in MG (-) thymomas, CD4+CD8+ thymocytes exhibited the opposite pattern of αß TCR and IL-7Rα expression. These results suggest that the positive and negative selection processes of CD4+CD8+ thymocytes might differ between MG (+) thymomas and MG (-) thymomas. The expression of the Helios transcription factor is induced during negative selection and marks a group of T cells that have undergone negative selection and are likely to be deleted due to strong TCR binding with self-peptides/MHC ligands. We observed that the percentage of Helios-positive CD4SP T cells was greater in MG (-) than in MG (+) thymomas. Thus, the differentially regulated selection process of CD4+CD8+ thymocytes, which involves TCR and IL-7/IL-7Rα signaling, is associated with the presence of MG in type B thymomas.
Assuntos
Miastenia Gravis , Receptores de Antígenos de Linfócitos T alfa-beta , Timócitos , Timoma , Humanos , Timoma/imunologia , Timoma/patologia , Timoma/metabolismo , Miastenia Gravis/imunologia , Miastenia Gravis/patologia , Miastenia Gravis/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Masculino , Timócitos/imunologia , Timócitos/metabolismo , Feminino , Pessoa de Meia-Idade , Receptores de Interleucina-7/metabolismo , Receptores de Interleucina-7/imunologia , Adulto , Idoso , Neoplasias do Timo/imunologia , Neoplasias do Timo/patologia , Neoplasias do Timo/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , ImunofenotipagemRESUMO
BACKGROUND: The object was to compare changes in patients undergoing lung surgery before and after COVID-19 outbreak, and to explore the impact of COVID-19 on lung surgery and its coping strategies. METHOD: A retrospective review of patients undergoing thoracic surgery at a single institution was conducted. Group A included patients treated between January 23, 2019, and January 23, 2020, while Group B included patients treated between June 1, 2020, and June 1, 2021, at our center. We compared the reasons of seeking medical treatment, the general characteristics of patients, imaging features, pathological features, surgical methods and postoperative recovery. RESULT: Compared to Group A, the number of patients with pulmonary nodules screened by routine check-up increased in Group B (57.6% vs 46.9%, p < 0.05). Female patient increased (55.2%vs 44.7%). Patient without smoking history or with family history of lung cancer increased (70.7% vs 60.7%) (10.1%vs 7.8%). Early stage lung cancer increased. Lobectomy decreased (53.4% vs 64.1%). Segmental resection increased (33.3% vs 12.7%). Patients without postoperative comorbidities increased (96.1%vs 85.7%). In the case of patients with Ground Glass Opacity(GGO), their age was comparatively lower (52 ± 9.9 vs. 55 ± 10.7), the female patients increased, patient without smoking history, tumor history, family history of tumor increased, small GGO increased. Lobectomy decreased (35.2% vs 49.7%). Segmental resection increased (49.6% vs 21.2%). Patients without postoperative comorbidities increased (96.5% vs 87.4%). CONCLUSION: Since COVID-19 outbreak, more young, non-smoking, female lung cancers, more Ground Glass Opacity, none high risk patients have been detected through screening, suggesting that our current screening criteria for lung cancer may need to be revised. Higher requirements, including the selection of the timing of nodular surgery, surgical methods were put forward for thoracic surgeons' skills.
Assuntos
COVID-19 , Neoplasias Pulmonares , Feminino , Humanos , China/epidemiologia , COVID-19/epidemiologia , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/cirurgia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Masculino , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
INTRODUCTION: SETD1A is upregulated in non-small cell lung cancer (NSCLC) tissues. This study investigated the molecular mechanism of the SETD1A/WTAPP1/WTAP axis in NSCLC. METHODS: Ferroptosis is a unique cell death mode driven by iron-reliant phospholipid peroxidation, which is regulated by multiple cellular metabolic pathways, including REDOX homeostasis, iron metabolism, mitochondrial activity and metabolism of amino acids, lipids and sugars. Thus, the levels of ferroptosis markers (MDA, SOD, GSH) were measured in vitro, and NSCLC cell behaviors were assessed. SETD1A-mediated H3K4me3 methylation was analyzed. SETD1A-exerted effects on ferroptosis and tumor growth in vivo were verified in nude mouse models. RESULTS: SETD1A was highly expressed in NSCLC cells. Silencing SETD1A suppressed NSCLC cell proliferation and migration, inhibited MDA, and enhanced GPX4, SOD, and GSH levels. SETD1A elevated WTAP expression through WTAPP1 upregulation by mediating H3K4me3 methylation in the WTAPP1 promoter region. WTAPP1 overexpression partly averted the promotional effect of silencing SETD1A on NSCLC cell ferroptosis. WTAP interference abrogated the inhibitory effects of WTAPP1 on NSCLC cell ferroptosis. Silencing SETD1A facilitated ferroptosis and accelerated tumor growth in nude mice through the WTAPP1/WTAP axis. CONCLUSION: SETD1A amplified WTAP expression through WTAPP1 upregulation by mediating H3K4me3 modification in the WTAPP1 promoter region, thus promoting NSCLC cell proliferation and migration and inhibiting ferroptosis.
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GSK3B is the mRNA form of glycogen synthase kinase 3 beta (GSK-3ß), which is a critical repressor of Wnt/ß-catenin signaling pathway and generally inhibited in cancer cells. Plenty of researches have disclosed that circular RNAs, namely circRNAs exert important functions in the progression of various human malignancies including lung adenocarcinoma (LUAD). Therefore, we attempted to explore whether there existed certain circRNAs that could mediate LUAD development by regulating GSK3B expression and Wnt/ß-catenin pathway. In the present research, circ-GSK3B (hsa_circ_0066903) was found to be significantly down-regulated in LUAD tissues and cells and it suppressed the proliferation, migration and stemness of LUAD cells. Furthermore, it was discovered that circ-GSK3B competitively sponged miR-3681-3p and miR-3909 to elevate GSK3B expression. Circ-GSK3B could impair the binding ability of FKBP51 to GSK-3ß to inhibit the phosphorylation of GSK-3ßS9, resulting in the inactivation of Wnt/ß-catenin signaling. In addition, the regulatory effect of circ-GSK3B on LUAD tumorigenesis and cell progression was testified through in vitro and in vivo rescue experiments. In conclusion, circ-GSK3B suppressed LUAD development through up-regulating and activating GSK3B.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs , Humanos , RNA Circular/genética , beta Catenina/genética , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Linhagem Celular Tumoral , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologiaRESUMO
A homogeneous polysaccharide (GLP), with an average molecular weight of 4.44 × 104 Da, was isolated and purified from the fruiting bodies of Ganoderma lucidum. In this work, we examined the antitumor activities of GLP using a mouse Lewis lung cancer (LLC) model and explored possible molecular pathways involved in its immunomodulatory mechanism on tumor-host interaction. GLP administration (25 and 100 mg/kg) significantly inhibited tumor growth, as evidenced by the decreased tumor volume and tumor weight, as well as histological features of tumor tissues with concomitant down-regulation of proliferating cell nuclear antigen (PCNA) proliferative marker. Less myeloid-derived suppressor cells (MDSCs) were accumulated in both spleen and tumor tissues from GLP-treated mice. In contrast, the percentage of CD4+ and CD8+ T cells together with the production of Th1-type cytokines (IFN-γ and IL-12) was increased in the spleen of LLC-bearing mice following GLP administration. Furthermore, GLP administration reversed the attenuated expression of CARD9, p-Syk and p-p65, and increased indoleamine 2,3-dioxygenase (IDO) protein expression in MDSCs of LLC-bearing mice. Collectively, our data demonstrated the first time that GLP induced the differentiation of MDSCs and inhibited the accumulation of MDSCs via CARD9-NF-κB-IDO pathway, thus prevented lung cancer development.
Assuntos
Antineoplásicos/farmacologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Polissacarídeos Fúngicos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Reishi , Animais , Antineoplásicos/isolamento & purificação , Carcinoma Pulmonar de Lewis/enzimologia , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Carpóforos , Polissacarídeos Fúngicos/isolamento & purificação , Masculino , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/enzimologia , Células Supressoras Mieloides/imunologia , NF-kappa B/metabolismo , Reishi/química , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Microambiente TumoralRESUMO
PURPOSE: To investigate the role of microRNA-122-5p in the pathogenesis of non-small cell lung cancer (NSCLC) and its underlying mechanism. METHODS: A total of 72 pairs of NSCLC tissues and paracancerous tissues were collected. The expression level of microRNA-122-5p in NSCLC tissues and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). The relationship between microRNA-122-5p expression and the clinical prognosis of NSCLC patients was then analyzed. Bioinformatics prediction and luciferase activity assay were performed to validate the direct binding of microRNA-122-5p and p53. Cell cycle, proliferation, and apoptosis were detected after microRNA-122-5p knockdown in NSCLC cells. The regulatory effect of microRNA-122-5p on promoting NSCLC development was detected by Western blot. RESULTS: MicroRNA-122-5p was more overexpressed in NSCLC tissues than in paracancerous tissues. MicroRNA-122-5p expression was negatively correlated with survival rate of NSCLC patients. Besides, microRNA-122-5p knockdown remarkably inhibited the proliferation and cell cycle advancement and increased apoptosis of NSCLC cells. Luciferase reporter gene assay and Western blot results indicated that microRNA-122-5p downregulated p53 and activated PI3K-AKT pathway, thereby promoting NSCLC development. CONCLUSION: MicroRNA-122-5p is overexpressed in NSCLC. Overexpression of microRNA-122-5p promotes NSCLC development by downregulating p53 and activating PI3K-AKT pathway.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genéticaRESUMO
The purpose of this study was to explore the internal mechanism of lung cancer under the action of caspase recruitment domain-containing protein 9 (CARD9) and immunosuppressive cells myeloid-derived suppressor cells (MDSCs) in the Lewis lung cancer mice model. In this research, mice were selected as research objects, and the mechanism of CARD9 and immunosuppressive cells MDSCs in lung cancer was studied by experimental methods such as mRNA expression level, HE staining of tumor cells, and electron microscopy. The results showed that CARD9 regulated lung cancer by controlling the working state of immunosuppressive cells MDSCs and its downstream product indoleamine 2, 3-dioxygenase (IDO). The study confirmed the tumor regulatory mechanism of CARD9-MDSCs-NF-KB-IDO in MDSCs under tumor environment. In summary, the mechanism of CARD9 and immunosuppressive cells MDSCs in lung cancer was to achieve the goal of tumor control through the control of downstream product IDO. There are still some shortcomings in the research process, but the research results still provide some guidance for future research. Therefore, it is a research topic with practical significance.
RESUMO
Tyrosine kinase inhibitors (TKIs) exert potent therapeutic efficacy in non-small cell lung cancers (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations. However, a major impediment for the effective treatment is the development of drug resistance. Some evidence supports a role for miRNAs in modulating NSCLC TKIs resistance. Here we show that miR-181a is significantly up-regulated in gefitinib-resistant cells compared with gefitinib-sensitive cells. Upregulation of miR-181a caused resistance of gefitinib, whereas downregulation of miR-181a sensitized NSCLC cells to gefitinib. Furthermore, the miR-181a plasma levels were significantly increased in acquired gefitinib resistant NSCLC patients compared with the plasma levels prior to gefitinib treatment in each patient. Bioinformatics analysis and luciferase reporter assay showed that growth arrest-specific 7 (GAS7) was a direct target gene of miR-181a. A significant inverse correlation between the expression of miR-181a and GAS7 was identified in NSCLC tissues. Downregulation of GAS7 expression could antagonize gefitinib re-sensitivity in PC9GR mediated by knockdown of miR-181a via AKT/ERK pathways and epithelial-to-mesenchymal transition markers. Additionally, GAS7 expression was downregulated in a large cohort of NSCLC patients, and a high mRNA level of GAS7 was associated with improved overall survival. Collectively, our findings provide a novel basis for using miR-181a/GAS7-based therapeutic strategies to reverse gefitinib resistance in NSCLC.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Quinazolinas/uso terapêutico , Biomarcadores Tumorais/metabolismo , China/epidemiologia , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Inibidores de Proteínas Quinases/toxicidade , Fatores de Risco , Taxa de SobrevidaRESUMO
OBJECTIVES: Lung-preserving surgery was proved to be effective and safe to treat patients with benign bronchial strictures. However, this surgical treatment has been rarely reported in patients with complete occlusion in the left main bronchus. The aim of this study was to assess the value of this procedure and report our experience in the treatment of these patients with left atelectasis caused by inflammatory bronchial occlusion. METHODS: We reviewed and analysed the medical records of 8 patients who had undergone left main bronchus sleeve resection for symptomatic left atelectasis caused by inflammatory bronchial occlusion from May 2007 to April 2011. RESULTS: Eight patients (3 men and 5 women) with a medical history of active pulmonary tuberculosis were involved in this study. The median age was 23 years. Parenchyma-sparing left main bronchus resection was performed in 4 patients, 1 of whom received partial wedge resection in the lingual lobe. Left main bronchus sleeve resection plus superior lobectomy was performed in 2 patients and left main bronchus sleeve resection plus left inferior lobectomy in 2 patients, 1 of whom received additional partial wedge resection of the lingual lobe. The procedure was completed successfully in all 8 patients without postoperative deaths. The mean follow-up time was 49.3 months, ranging from 23 to 69 months. No major complications, including stenosis and atelectasis, were observed during the follow-up period. The symptoms of pulmonary atelectasis disappeared and pulmonary ventilation function improved significantly. CONCLUSIONS: In symptomatic patients with left atelectasis caused by inflammatory bronchial occlusion, lung-preserving surgery is an effective and safe surgical treatment.
Assuntos
Obstrução das Vias Respiratórias/cirurgia , Bronquite/complicações , Tratamentos com Preservação do Órgão/métodos , Pneumonectomia/métodos , Atelectasia Pulmonar/cirurgia , Adolescente , Adulto , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/fisiopatologia , Bronquite/diagnóstico , Bronquite/fisiopatologia , Broncoscopia , Constrição Patológica , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Atelectasia Pulmonar/diagnóstico , Atelectasia Pulmonar/etiologia , Atelectasia Pulmonar/fisiopatologia , Ventilação Pulmonar , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Capacidade Pulmonar Total , Resultado do Tratamento , Adulto JovemRESUMO
Mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a widespread environmental contaminant and has been proved to have potential adverse effects on the reproductive system, carcinogenicity, liver, kidney and developmental toxicities. However, the effect of MEHP on vascular system remains unclear. The main purpose of this study was to evaluate the cytotoxic effects of MEHP on human umbilical endothelial cells (HUVEC) and its possible molecular mechanism. HUVEC cells were treated with MEHP (0, 6.25, 12.5, 25,50 and 100 µM), and the cellular apoptosis and mitochondrial membrane potential as well as intracellular reactive oxygen species were determined. In present study, MEHP induced a dose-dependent cell injury in HUVEC cell via an apoptosis pathway as characterized by increased percentage of sub-G1, activation of caspase-3, -8 and -9, and increased ratio of Bax/bcl-2 mRNA and protein expression as well as cytochrome C releasing. In addition, there was obvious oxidative stress, represented by decreased glutathione level, increased malondialdehyde level and superoxide dismutase activity. N-Acetylcysteine, as an antioxidant that is a direct reactive oxygen species scavenger, could effectively block MEHP-induced reactive oxygen species generation, mitochondrial membrane potential loss and cell apoptosis. These data indicated that MEHP induced apoptosis in HUVEC cells through a reactive oxygen species-mediated mitochondria-dependent pathway.
Assuntos
Dietilexilftalato/análogos & derivados , Poluentes Ambientais/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocromos c/biossíntese , Dietilexilftalato/toxicidade , Glutationa/metabolismo , Humanos , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as gefitinib are clinically effective treatments for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, therapeutic effect is ultimately limited by the development of acquired TKI resistance. MicroRNAs (miRNAs) represent a category of small non-coding RNAs commonly deregulated in human malignancies. The aim of this study was to investigate the role of miRNAs in gefitinib resistance. We established a gefitinib-resistant cell model (PC9GR) by continually exposing PC9 NSCLC cells to gefitinib for 6 months. MiRNA microarray screening revealed miR-138-5p showed the greatest downregulation in PC9GR cells. Re-expression of miR-138-5p was sufficient to sensitize PC9GR cells and another gefitinib-resistant NSCLC cell line, H1975, to gefitinib. Bioinformatics analysis and luciferase reporter assay showed that G protein-coupled receptor124 (GPR124) was a direct target of miR-138-5p. Experimental validation demonstrated that expression of GPR124 was suppressed by miR-138-5p on protein and mRNA levels in NSCLC cells. Furthermore, we observed an inverse correlation between the expression of miR-138-5p and GPR124 in lung adenocarcinoma specimens. Knockdown of GPR124 mimicked the effects of miR-138-5p on the sensitivity to gefitinib. Collectively, our results suggest that downregulation of miR-138-5p contributes to gefitinib resistance and that restoration of miR-138-5p or inhibition GPR124 might serve as potential therapeutic approach for overcoming NSCLC gefitinib resistance.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Quinazolinas/farmacologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Gefitinibe , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidoresRESUMO
This paper presents a comparative study on the antifouling properties of poly(ethylene glycol) (PEG)-based polymer coatings prepared by surface-initiated polymerization (SIP). Three types of poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMEMA) polymer thin films of approximate 100 nm thickness were grafted from a catechol initiator that was immobilized on a Ti substrate. OEGMEMA monomers containing side chains of 4, 9, and 23 EG units were used in surface-initiated atom transfer radical polymerization (SI-ATRP) to form POEGMEMA-4, -9, and -23 polymer brushes. The chemical composition, thickness, and wettability of the polymer brushes were characterized by X-ray photoelectron spectroscopy (XPS), ellipsometry, and static water contact angle measurements, respectively. The dependence of antifouling performance on EG side chain length was systemically tested and compared by 3T3 fibroblast cell adhesion assays. Results from 4-h cell culture experiments revealed the complete absence of cell attachment on all the grafted Ti substrates. Excellent cell fouling resistance continued with little dependence on EG side chain length up to three weeks, after which long-term antifouling performance depended on the EG chain length as the grafted samples reached confluent cell coverage in 7, 10, and 11 weeks for POEGMEMA-4, -9, and -23, respectively.