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AIMS: Treatment resistance commonly emerges in small cell lung cancer (SCLC), necessitating the development of novel and effective biomarkers to dynamically assess therapeutic efficacy. This study aims to evaluate the clinical utility of aneuploid circulating tumor cells (CTCs) for risk stratification and treatment response monitoring. METHODS: A total of 126 SCLC patients (two cohorts) from two independent cancer centers were recruited as the study subjects. Blood samples were collected from these patients and aneuploid CTCs were detected. Aneuploid CTC count (ACC) and aneuploid CTC score (ACS), were used to predict progression-free survival (PFS) and overall survival (OS). The performance of the ACC and the ACS was evaluated by calculating the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Compared to ACC, ACS exhibited superior predictive power for PFS and OS in these 126 patients. Moreover, both univariate and multivariate analyses revealed that ACS was an independent prognostic factor. Dynamic ACS changes reflected treatment response, which is more precise than ACC changes. ACS can be used to assess chemotherapy resistance and is more sensitive than radiological examination (with a median lead time of 2.8 months; P < 0.001). When patients had high ACS levels (> 1.115) at baseline, the combination of immunotherapy and chemotherapy resulted in longer PFS (median PFS, 7.7 months; P = 0.007) and OS (median OS, 16.3 months; P = 0.033) than chemotherapy alone (median PFS, 4.9 months; median OS, 13.6 months). CONCLUSIONS: ACS could be used as a biomarker for risk stratification, treatment response monitoring, and individualized therapeutic intervention in SCLC patients.
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Aneuploidia , Biomarcadores de Tumor , Resistencia a Antineoplásicos , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Carcinoma Pulmonar de Células Pequeñas , Humanos , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/sangre , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Anciano , Supervivencia sin Progresión , AdultoRESUMEN
OBJECTIVE: To investigate the effectiveness of a CTC-based classifier in stratifying stage IB LUAD. SUMMARY OF BACKGROUND DATA: Stage IB LUADs have an approximately 70% 5-year survival rate. The clinical application of ACT is controversial due to inconsistent results in a series of trials and few useful guide biomarkers. Thus, there is a pressing need for robust biomarkers to stratify stage IB patients to define which group would most likely benefit from ACT. Methods: Two hundred twelve stage IB LUAD patients were enrolled and were divided into 3 independent cohorts. The aptamer-modified NanoVelcro system was used to enrich the CTCs. RESULTS: A cutoff of <4 or >4 CTCs as the optimal prognostic threshold for stage IB LUAD was generated to stratify the patients in a 70-patient cohort into low-risk and high-risk groups. Patients with ≥ 4 CTCs in the training cohort had shorter progression-free survival ( P < 0.0001) and overall survival ( P < 0.0001) than patients with <4 CTCs. CTC number remained the strongest predictor of progression-free survival and overall survival even in a multivariate analysis including other clinicopathological parameters. Furthermore, a nomogram based on the CTC count was developed to predict the 3-year and 5-year survival in the training cohort and performed well in the other 2 validation cohorts (C-index: 0.862, 0.853, and 0.877). CONCLUSION: The presence of >4 CTCs can define a high-risk subgroup, providing a new strategy to make optimal clinical decisions for stage IB LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Humanos , Relevancia Clínica , Estudios de CohortesRESUMEN
BACKGROUND: Oxidative stress plays an important role in the progression of various types of tumors. However, its role in esophageal squamous cell carcinoma (ESCC) has seldom been explored. This study aimed to discover prognostic markers associated with oxidative stress in ESCC to improve the prediction of prognosis and help in the selection of effective immunotherapy for patients. RESULTS: A consensus cluster was constructed using 14 prognostic differentially expressed oxidative stress-related genes (DEOSGs) that were remarkably related to the prognosis of patients with ESCC. The infiltration levels of neutrophils, plasma cells, and activated mast cells, along with immune score, stromal score, and estimated score, were higher in cluster 1 than in cluster 2. A prognostic signature based on 10 prognostic DEOSGs was devised that could evaluate the prognosis of patients with ESCC. Calculated risk score proved to be an independent clinical prognostic factor in the training, testing, and entire sets. P53 signaling pathway was highly enriched in the high-risk group. The calculated risk score was positively related to the infiltration levels of resting mast cells, memory B cells, and activated natural killer (NK) cells and negatively associated with the infiltration levels of M1 and M2 macrophages. The relationship between clinical characteristics and risk score has not been certified. The half-maximal inhibitory concentration (IC50) values for sorafenib and gefitinib were lower for patients in the low-risk group. CONCLUSION: Our prognostic signature based on 10 prognostic DEOSGs could predict the disease outcomes of patients with ESCC and had strong clinical value. Our study improves the understanding of oxidative stress in tumor immune microenvironment (TIME) and provides insights for developing improved and efficient immunotherapy strategies.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Gefitinib , Humanos , Estrés Oxidativo , Pronóstico , Sorafenib , Microambiente Tumoral/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: General transcription factor IIi (GTF2I) mutations are very common in thymic epithelial tumors (TETs) and are related to a more favorable prognosis in TET patients. However, limited research has been conducted on the role of GTF2I in the tumor immune microenvironment (TIME). Further, long non-coding RNAs (lncRNAs) have been associated with the survival of patients with TETs. Therefore, this study aimed to explore the relationship between GTF2I mutations and TIME and build a new potential signature for predicting tumor recurrence in the TETs. Research data was downloaded from The Cancer Genome Atlas database and the CIBERSORT algorithm was used to evaluate TIME differences between GTF2I mutant and wild-type TETs. Relevant differentially expressed lncRNAs based on differentially expressed immune-related genes were identified to establish lncRNA pairs. We constructed a signature using univariate and multivariate Cox regression analyses. RESULTS: GTF2I is the most commonly mutated gene in TETs, and is associated with an increased number of early-stage pathological types, as well as no history of myasthenia gravis or radiotherapy treatment. In the GTF2I wild-type group, immune score and immune cell infiltrations with M2 macrophages, activated mast cells, neutrophils, plasma, T helper follicular cells, and activated memory CD4 T cells were higher than the GTF2I mutant group. A risk model was built using five lncRNA pairs, and the 1-, 3-, and 5-year area under the curves were 0.782, 0.873, and 0.895, respectively. A higher risk score was related to more advanced histologic type. CONCLUSION: We can define the GTF2I mutant-type TET as an immune stable type and the GTF2I wild-type as an immune stressed type. A signature based on lncRNA pairs was also constructed to effectively predict tumor recurrence.
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Neoplasias Glandulares y Epiteliales , ARN Largo no Codificante , Factores Generales de Transcripción , Factores de Transcripción TFIII , Factores de Transcripción TFII , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación , Recurrencia Local de Neoplasia/genética , Neoplasias Glandulares y Epiteliales/genética , Pronóstico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias del Timo , Factores Generales de Transcripción/genética , Factores Generales de Transcripción/metabolismo , Factores de Transcripción TFII/genética , Factores de Transcripción TFII/metabolismo , Factores de Transcripción TFIII/genética , Factores de Transcripción TFIII/metabolismo , Microambiente TumoralRESUMEN
OBJECTIVES: To develop and validate a radiomics model for evaluating treatment response to immune-checkpoint inhibitor plus chemotherapy (ICI + CT) in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: A total of 64 patients with advance ESCC receiving first-line ICI + CT at two centers between January 2019 and June 2020 were enrolled in this study. Both 2D ROIs and 3D ROIs were segmented. ComBat correction was applied to minimize the potential bias on the results due to different scan protocols. A total of 788 features were extracted and radiomics models were built on corrected/uncorrected 2D and 3D features by using 5-fold cross-validation. The performance of the radiomics models was assessed by its discrimination, calibration and clinical usefulness with independent validation. RESULTS: Five features and support vector machine algorithm were selected to build the 2D uncorrected, 2D corrected, 3D uncorrected and 3D corrected radiomics models. The 2D radiomics models significantly outperformed the 3D radiomics models in both primary and validation cohorts. When ComBat correction was used, the performance of 2D models was better (p = 0.0059) in the training cohort, and significantly better (p < 0.0001) in the validation cohort. The 2D corrected radiomics model yielded the optimal performance and was used to build the nomogram. The calibration curve of the radiomics model demonstrated good agreement between prediction and observation and the decision curve analysis confirmed the clinical utility. CONCLUSIONS: The easy-to-use 2D corrected radiomics model could facilitate noninvasive preselection of ESCC patients who would benefit from ICI + CT.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Máquina de Vectores de Soporte , Anticuerpos Monoclonales Humanizados/administración & dosificación , Sesgo , Biomarcadores de Tumor , Carboplatino/administración & dosificación , Terapia Combinada/métodos , Docetaxel/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nomogramas , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a common malignant carcinoma of digestive system with high mortality. RAB, member RAS oncogene family like 6 (RABL6), a member of the RAS subfamily, has been reported as an important molecule in several cancers. However, its potential role in ESCC still remains unclear. METHODS: RABL6 mRNA expression was detected in 93 frozen ESCC samples using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Immunohistochemistry was applied to evaluate the RABL6 expression in tissue microarray containing 171 pairs of ESCC tissues and paired para-cancerous tissues. We evaluated RABL6 expression and its correlation with clinicopathological characteristics and survival. Subsequently, the impact of RABL6 knockdown on the ability of cell proliferation, apoptosis, migration and epithelial-mesenchymal transition (EMT) of ESCC cells was investigated by MTS, Focus formation, flow cytometry, Transwell assays, qRT-PCR, western blot, inverted microscope observation and phalloidin staining, respectively. RESULTS: Compared to paired para-cancerous tissues, RABL6 was highly expressed in ESCC. The RABL6 high-expression was associated with worse prognosis. We also revealed silencing of RABL6 caused inhibition of cell proliferation, invasion and migration. Further experiments demonstrated that knockdown of RABL6 suppressed the aggressive biological activities of ESCC by suppressing EMT in ESCC cells. CONCLUSIONS: RABL6 functions as a tumor oncogene in ESCC. It would be a potential biomarker predicting prognosis, and a novelty target for ESCC therapy.
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Biomarcadores de Tumor/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Esófago/patología , Proteínas Oncogénicas/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Proteínas Oncogénicas/genética , Pronóstico , Análisis de Matrices Tisulares , Proteínas de Unión al GTP rab/genéticaRESUMEN
BACKGROUND: This study aimed to investigate the prognostic value of the potential biomarker collagen triple helix repeat containing 1 (CTHRC1) in lung adenocarcinoma (LUAD) patients. METHODS: A total of 210 LUAD patients diagnosed between 2003 and 2016 in the Department of Pathology of the First Affiliated Hospital of Sun Yat-sen University were included in this study. The expression of CTHRC1 and vascular endothelial growth factor (VEGF), and microvessel density (MVD, determined by CD34 immunostaining) were evaluated by immunohistochemistry in LUAD tissues. The association between the expression of these proteins and clinicopathological features or clinical outcomes was analyzed. RESULTS: Here, we confirmed that CTHRC1 expression was associated with prognosis and can serve as a significant predictor for overall survival (OS) and progression-free survival (PFS) in LUAD. Additionally, we observed that CTHRC1 expression was positively associated with tumor angiogenesis markers, such as VEGF expression (P < 0.001) and MVD (P < 0.01). Then, we performed gene set enrichment analysis (GESA) and cell experiments to confirm that enhanced CTHRC1 expression can promote VEGF levels. Based on and cox regression analysis, a predictive model that included CTHRC1, VEGF and MVD was constructed and confirmed as a more accurate independent predictor for OS (P = 0.001) and PFS (P < 0.001) in LUAD than other parameters. CONCLUSIONS: These results demonstrated that high CTHRC1 expression may be closely related to tumor angiogenesis and poor prognosis in LUAD. The predictive model based on the CTHRC1 level and tumor angiogenesis markers can be used to predict LUAD patient prognosis more accurately.
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BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer with high aggressiveness and poor prognosis. There is an urgent need for understanding the molecular mechanism underlying the development and progression of ESCC. METHODS: ESCC tissues and corresponding non-neoplastic tissues were collected. The expression and function of miR-124-3p and BCAT1 in two cell lines KYSE-150 and Eca109 were determined. RESULTS: We show downregulation of miR-124-3p expression in ESCC tissues, which is highly correlated with proliferation and migration of ESCC cell lines KYSE-150 and Eca109. miR-124-3p show high correlation with TNM stage and differentiation grade. Furthermore, miR-124-3p directly targets mRNA 3'UTR region of BCAT1, which results in upregulation of BCAT1 expression as observed in ESCC tissues and cell lines. Also, our data indicates that BCAT1 high expression is strongly linked to the disease-free survival, tumor size, pathologic stage, T classification and differentiation grade. On the other hand, we clarified the upstream mechanism regulating miR-124-3p expression in ESCC, which involves in the hypermethylation-silencing regulation mediated by DNA methyltransferase 1(DNMT1), which is of high expression in ESCC tissues and cell lines in the present study. In addition, DNMT1 knockdown or inhibition of DNMT1 function contributes to downregulation of miR-124-3p and BCAT1 expression. CONCLUSIONS: Our study thus clarifies a new mechanism that DNMT1/miR-124/BCAT1 axis regulates the development and progression of ESCC.
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ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Transaminasas/metabolismo , Regiones no Traducidas 3' , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , ADN (Citosina-5-)-Metiltransferasa 1/genética , Metilación de ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Invasividad Neoplásica/fisiopatología , Estadificación de Neoplasias , Transaminasas/genética , TransfecciónRESUMEN
BACKGROUND: As there is no consensus on the optimal surgery strategy for multiple primary lung cancer (MPLC), we conducted this study to address this issue by comparing the prognosis of MPLC patients underwent different surgical strategies including sublobar resection and the standard resection through a systemic review and meta-analysis. METHODS: Relevant literature was obtained from three databases including PubMed, Embase and Web of Science. Inclusion and exclusion criteria were set for the screening of articles to be selected for further conduction of systemic review and meta-analysis. The HRs of OS of the sublobar group compared with standard resection group were extracted directly or calculated indirectly from included researches. RESULTS: Ten researches published from 2000 to 2017 were included in this study, with 468 and 445 MPLC cases for the standard resection group and sublobar resection group respectively. The result suggested that OS of MPLC patients underwent sublobar resection (segmentectomy or wedge resection for at least one lesion) was comparable with those underwent standard resection approach (lobectomy or pneumonectomy for all lesions), with HR 1.07, 95% CI 0.67-1.71, p = 0.784. Further analysis found no difference in subgroups of synchronous and metachronous (from second metachronous lesion), different population region and dominant sex type. CONCLUSIONS: This study may reveal that sublobar resection is acceptable for patients with MPLC at an early stage, because of the equivalent prognosis to the standard resection and better pulmonary function preservation. Further research is needed to validate these findings.
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Neoplasias Pulmonares/cirugía , Neoplasias Primarias Múltiples/cirugía , Neumonectomía/métodos , Humanos , Estadificación de Neoplasias , PronósticoRESUMEN
OBJECTIVES: There is no consensus on the effectiveness of prophylactic thoracic duct ligation (PLG) in esophagectomy for reducing the incidence of postoperative chylothorax. We performed a systemic review and meta-analysis to study its efficacy. METHODS: A systemic review of the publications was performed on three databases to identify all the relevant literature on comparative outcomes of PLG and nonprophylactic thoracic duct ligation (NPLG). The primary end point was the incidence of postoperative chylothorax. RESULTS: Seven studies with comparative data on PLG (n = 2,178) versus NPLG (n = 3,048) were identify from the current publications. Comparison showed no significant difference between PLG and NPLG on the incidence of postoperative chylothorax (relative risk = 0.431; 95% confidence interval, 0.186 to 1.002; p = 0.050). CONCLUSIONS: Although some studies showed that PLG during the esophagectomy was effective to lower the incidence of postoperative chylothorax, no evidence was observed in the present meta-analysis. Further research is warranted to validate the findings.
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Quilotórax/prevención & control , Esofagectomía/efectos adversos , Conducto Torácico/cirugía , Quilotórax/diagnóstico , Quilotórax/epidemiología , Humanos , Incidencia , Ligadura , Modelos Lineales , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: The use of thymectomy in myasthenia gravis (MG) patients with a history of myasthenic crisis (MC) has not been well established. Here, we determined the efficacy of thymectomy by assessing the long-term clinical outcomes and reviewed thymectomy reports on MC patients. METHODS: Subjects included 31 patients who suffered at least one crisis before surgery, with a cumulative total 73 episodes of MC in Southern China between May 2000 and December 2010. Long-term follow-up was performed and clinical outcomes were evaluated. We used complete stable remission (CSR), termed an asymptomatic status without medication for at least 12 months; general complete remission (GCR), termed an asymptomatic status with or without some form of therapy excluding cholinesterase inhibitors, to assess patient outcomes. RESULTS: All patients underwent thymectomy with an overall complication rate of 16.1 % and a perioperative mortality rate of 3.2 %. Long-term follow-up occurred between 12.6 and 177 months, at which point 18 (58.1 %) patients experienced improved status, including one patient who achieved CSR; 13 (41.9 %) patients achieved GCR; 6 (19.4 %) showed unchanged status and one worse (3.2 %) status. The remaining 6 patients died, with 3 due to MG-related causes. Using a multivariate Cox regression analysis of GCR by characteristics, patients with better response to medical treatments before thymectomy were positively associated with GCR rates (p = 0.028). CONCLUSIONS: Extended transsternal thymectomy is a feasible and effective therapy for MG patients with crisis history, especially for those patients who have shown positive signs of remission after exhausting conventional medical treatments.
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Miastenia Gravis/cirugía , Timectomía , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/complicaciones , Miastenia Gravis/fisiopatología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The Aurora-A (Aur-A) gene, a key regulator of mitosis, has been proved as an oncogene in a variety of cancers. The Aur-A overexpression has been proved correlated with aggressiveness of cancer cells. However, the frequency of Aur-A protein overexpression, as well as its association with clinicopathologic parameters and prognosis remain unclear in lung adenocarcinoma (ADC). This study tried to clarify the clinical significance of Aur-A in patients with resected lung ADC. PATIENTS AND METHODS: A total of 142 informative patients with surgically resected lung ADC and 20 normal lung tissues were enrolled. Western blot and immunohistochemistry (IHC) were utilized to assess protein expression of Aur-A. RESULT: The expression of Aur-A was elevated in most of tumor tissues compared with the adjacent tissues by western blot. The IHC results showed that Aur-A protein was over-expressed in 98 of 142 (69.0%) tumor sections, while Aur-A was low-expressed in all normal lung sections. A positive correlation between Aur-A overexpression rate and ascending pathologic stages was observed (P<0.05). Kaplan-Meier analysis demonstrated that patients with Aur-A high expression had significantly inferior survival compared to those with Aur-A low expression. Both overall survival (OS) and disease-free survival (DFS) of positive overexpression patients were shorter than the negative group (P=0.036, P=0.041, respectively). Multivariate analysis confirmed that Aur-A expression, as an independent and significant factor for both DFS and OS, could predict a poor prognosis in patients with resected lung ADC (P=0.022, P=0.049, respectively). CONCLUSIONS: Aur-A was overexpressed in lung ADC and overexpression of Aur-A might be a novel predictor for poor prognosis and potential therapeutic target in lung ADC.
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BACKGROUND: This study aimed to identify the key genes involved in the development of multiple primary lung cancers. METHODS: Differential expression analysis was performed, followed by comparing the infiltration levels of 22 immune cell types between multiple and single primary lung adenocarcinomas. Marker genes for epithelial cells with different proportions between the two types of lung adenocarcinomas were identified. The common genes between the marker genes and differentially expressed genes were identified. Finally, the effects of the key genes were tested on the in vitro proliferation, migration and morphology. RESULTS: The infiltration levels of helper follicular T cells, resting NK cells, activated NK cells, M2 macrophages and resting mast cells were higher in the patients with multiple than in those with single primary lung adenocarcinomas. A total of 1553 differentially expressed genes and 4414 marker genes of epithelial cells were identified. Logistic regression analysis was performed on the 164 resulting genes. The macrophage migration inhibitory factor expression was positively associated with the occurrence of multiple primary lung adenocarcinomas. Moreover, its signalling pathway was the key pathway among the epithelial cells and multiple and single primary lung adenocarcinoma cells, and it was upregulated in lung adenocarcinoma cells. It also increased the expression of lung cancer markers, including NES and CA125, induced morphological changes in alveolar epithelial type II cells, and promoted their proliferation, migration and invasion. CONCLUSIONS: Multiple and single primary lung adenocarcinomas have different tumour immune microenvironments, and migration inhibitory factor may be a key factor in the occurrence of multiple primary lung adenocarcinomas.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Factores Inhibidores de la Migración de Macrófagos , Neoplasias Primarias Múltiples , Humanos , Factores Inhibidores de la Migración de Macrófagos/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Microambiente Tumoral/genéticaRESUMEN
Hypothyroidism has been suggested to play a role in tumor progression. However, the causal association between hypothyroidism and lung cancer remains unknow. To elucidate the potential association between hypothyroidism and lung cancer risk, we employ a Mendelian randomization (MR) approach. MR was performed to analyze pooled data from the International Lung Cancer Consortium (11,348 cases and 15,861 controls; European ancestry) to determine the causal relationship between hypothyroidism and lung cancer. We used 36, 83, and 14 single nucleotide polymorphisms as instrumental variables for hypothyroidism/myxoedema, hypothyroidism, and exercise, respectively. We further investigated the mechanisms involved in transcriptome analysis using data from The Cancer Genome Atlas and Genotype-Tissue Expression database. We conducted an initial validation of intermediary factor using a two-step MR analysis. Genetically predicted hypothyroidism was significantly related to the risk of overall lung cancer, specifically the risk of lung squamous cell cancer (LSCC) but not with the risk of lung adenocarcinoma (LUAD) as assessed using the inverse-variance weighted (IVM) method. A similar causal association was found between hypothyroidism/myxoedema and the risk of lung cancer, LSCC, and LUAD. Transcriptome analysis showed that genes associated with hypothyroidism, lung cancer, and LSCC were enriched in the PI3K/Akt signaling pathway and oxidative stress response. However, genes related to hypothyroidism and LUAD did not exhibit enrichment in these pathways. Hypothyroidism was significantly associated with strenuous sports or other exercises. Moreover, genetically predicted exercise was significantly related to the risk of overall lung cancer, and LSCC, but not LUAD. We detected no horizontal pleiotropy using the MR-PRESSO and MR Egger regression intercept. Hypothyroidism was causally associated with a lower risk of lung cancer, and these effects might be mediated by the oxidative stress response and the PI3K/Akt signaling pathway. Therefore, our study suggests that the potential factors and viable etiologies of hypothyroidism that contributed to lung cancer risk deserve further investigation.
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The improvement of treatment for patients with 'driver-gene-negative' lung adenocarcinoma (LUAD) remains a critical problem to be solved. We aimed to explore the role of methylation of N6 adenosine (m6A)-related long noncoding RNA (lncRNA) in stratifying 'driver-gene-negative' LUAD risk. Patients negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as 'driver-gene-negative' cases. RNA sequencing was performed in 46 paired tumors and adjacent normal tissues from patients with 'driver-gene-negative' LUAD. Twenty-three m6A regulators and relevant lncRNAs were identified using Pearson's correlation analysis. K-means cluster analysis was used to stratify patients, and a prognostic nomogram was developed. The CIBERSORT and pRRophetic algorithms were employed to quantify the immune microenvironment and chemosensitivity. We identified two clusters highly consistent with the prognosis based on their unique expression profiles for 46 m6AlncRNAs. A risk model constructed from nine m6A lncRNAs could stratify patients into high- and low-risk groups with promising predictive power (C-index = 0.824), and the risk score was an independent prognostic factor. The clusters and risk models were closely related to immune characteristics and chemosensitivity. Additional pan-cancer analysis using the nine m6AlncRNAs showed that the expression of DIO3 opposite strand upstream RNA (DIO3OS) is closely related to the immune/stromal score and tumor stemness in a variety of cancers. Our results show that m6AlncRNAs are a reliable prognostic tool and can aid treatment decision-making in 'driver-gene-negative' LUAD. DIO3OS is associated with the development of various cancers and has potential clinical applications.
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Adenocarcinoma , Neoplasias Pulmonares , ARN Largo no Codificante , Humanos , Metilación , ARN Largo no Codificante/genética , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Adenosina , Pulmón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMEN
OBJECTIVE: Examining the role of immune-related genes (IRGs) in "driver gene negative" lung adenocarcinoma (LUAD) may provide new ideas for the treatment and study for this LUAD subgroup. We aimed to find the hub immune-related gene pairs can stratify the risk of "driver-gene-negative" LUAD. MATERIALS AND METHODS: IRGs were identified according to ImmPort database based on RNA sequencing results of tumors and normal tissues from 46 patients with "driver gene negative" LUAD at The First Affiliated Hospital of Sun Yat-sen University and cyclically singly paired as immune-related gene pairs (IRGPs). Multivariate Cox analysis was used to construct an immune risk model and a prognostic nomogram combining was also been developed. Immune microenvironment landscape described by CIBERSORT and drug sensitivity calculated by pRRophetic algorithm were used to explore possible treatment improvements. RESULTS: A novel immune risk model with 5-IRGPs (CD1A|CXCL135, CD1A|S100A7L2, IFNA7|CMTM2, IFNA7|CSF3, CAMP|TFR2) can accurately distinguish patients in the high- and low-risk groups. Risk score act as an independent prognostic factor and is related to clinical stage. There are significant differences in tumor immune microenvironment and PD-1/PD-L1/CTLA-4 expression between groups. The low-risk patient may benefit more from the commonly used chemotherapy regimens such as gemcitabine and paclitaxel. CONCLUSION: This study constructed 5-IRGPs as a reliable prognostic tool and may represent genes pairs that are potential rationale for choice of treatment for "driver gene negative" LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Biomarcadores de Tumor/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Nomogramas , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
Oesophageal squamous cell carcinoma (ESCC) remains a clinically challenging disease with high morbidity rates and poor prognosis. ESCC is also the most common pathological type of oesophageal cancer (EC) in China. Ras-related genes are one of the most frequently mutated gene families in cancer and regulate tumour development and progression. Given this, we investigated the Ras-related gene expression profiles and their values in ESCC prognosis, using data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. We found that we could identify three distinct oesophageal cancer clusters based on their unique expression profile for 11 differentially expressed Ras-related genes with each of these demonstrating some prognostic value when, evaluated using univariate Cox analysis. We then used multivariate Cox analysis to identify relevant independent prognostic indicators and used these to build a new prognostic prediction model for oesophageal cancer patients using these three Ras-related genes. These evaluations produced an area under the curve (AUC) of 0.932. We found that our Ras-related signatures could also act as independent factors in ESCC prognosis and that patients with low Ras scores showed a higher overall expression levels of various immune checkpoint genes, including TNFSF4, TNFRSF8, TNFRSF9, NRP1, CD28, CD70, CD200, CD276, METTL16, METTL14, ZC3H13, YTHDF3, VIRMA, FTO, and RBM15, as well as a higher CSMD3, FLG, DNAH5, MUC4, PLCO, EYS, and ZNF804B mutation rates, and better sensitivity to drugs such as erlotinib, paclitaxel, and gefitinib. In conclusion, we were able to use the unique expression profiles of several Ras-related genes to produce a novel disease signature which might facilitate improved prognosis in ESCC, providing new insight into both diagnosis and treatment in these cancers.
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INTRODUCTION: Our previous study showed that naringin (NRG) protects cardiomyocytes against high glucose (HG)-induced injuries by inhibiting p38 mitogen-activated protein kinase (MAPK). Leptin induces hypertrophy in rat cardiomyocytes via p38/MAPK activation. The present study aimed to test the hypothesis that leptin-Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3), which are responsible for leptin's functions, are involved in HG-induced injuries and cardioprotective effects of NRG in cardiomyocytes. MATERIAL AND METHODS: H9c2 cells were exposed to HG for 24 h to establish a cardiomyocyte injury model. Cells were pretreated with NRG and other drugs before exposure to HG. Protein expression was measured by western blot analysis. Cell viability was detected by Cell Counting Kit-8 assay. Apoptotic cells were assessed by Hoechst 33258 staining assay. Intracellular reactive oxygen species levels were determined by dichlorofluorescein diacetate staining. Mitochondrial membrane potential was evaluated using JC-1. An enzyme-linked immunosorbent assay was performed to determine the inflammatory cytokines. RESULTS: NRG significantly attenuated HG-induced increases in leptin and Ob-R expression. Pretreatment with either a leptin antagonist (LA) or NRG markedly ameliorated HG-induced elevation of phosphorylated (p)-JAK2 and p-STAT3, respectively. Pretreatment with NRG, LA, Ob-R antagonist, or AG490 clearly alleviated HG-induced injuries and inflammation. CONCLUSIONS: This study provides new evidence of the NRG protective effects of H9c2 cells against HG-induced injuries possibly via modulation of the leptin-JAK2/STAT3 pathway.
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Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma.
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Adenocarcinoma del Pulmón/fisiopatología , Mitocondrias/efectos de los fármacos , Triterpenos Pentacíclicos/efectos adversos , Tripterygium/efectos adversos , Movimiento Celular , Proliferación Celular , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Transducción de Señal , TransfecciónRESUMEN
BACKGROUND: Accurate thymoma staging via computed tomography (CT) images is difficult even for experienced thoracic doctors. Here we developed a preoperative staging tool differentiating Masaoka-Koga (MK) stage I patients from stage II patients using CT images. METHODS: CT images of 174 thymoma patients were retrospectively selected. Two chest radiologists independently assessed the images. Variables with statistical differences in univariate analysis were adjusted for age, sex, and smoking history in multivariate logical regression to determine independent predictors of the thymoma stage. We established a deep learning (DL) 3D-DenseNet model to distinguish the MK stage I and stage II thymomas. Furthermore, we compared two different methods to label the regions of interest (ROI) in CT images. RESULTS: In routine CT images, there were statistical differences (P<0.05) in contour, necrosis, cystic components, and the degree of enhancement between stage I and II disease. Multivariate logical regression showed that only the degree of enhancement was an independent predictor of the thymoma stage. The area under the receiver operating characteristic curve (AUC) of routine CT images for classifying thymoma as MK stage I or II was low (AUC =0.639). The AUC of the 3D-DenseNet model showed better performance with a higher AUC (0.773). ROIs outlined by segmentation labels performed better (AUC =0.773) than those outlined by bounding box labels (AUC =0.722). CONCLUSIONS: Our DL 3D-DenseNet may aid thymoma stage classification, which may ultimately guide surgical treatment and improve outcomes. Compared with conventional methods, this approach provides improved staging accuracy. Moreover, ROIs labeled by segmentation is more recommendable when the sample size is limited.