RESUMO
Eph receptors constitute the largest family of receptor tyrosine kinases, comprising 14 distinct members classified into two subgroups: EphAs and EphBs.. Despite their essential functions in normal physiological processes, accumulating evidence suggests that the involvement of the Eph family in cancer is characterized by a dual and often contradictory nature. Research indicates that Eph/ephrin bidirectional signaling influences cell-cell communication, subsequently regulating cell migration, adhesion, differentiation and proliferation. The contradictory functionalities may arise from the diversity of Eph signaling pathways and the heterogeneity of different cancer microenvironment. In this review, we aim to discuss the dual role of the Eph receptors in tumor development, attempting to elucidate the paradoxical functionality through an exploration of Eph receptor signaling pathways, angiogenesis, immune responses, and more. Our objective is to provide a comprehensive understanding of the molecular mechanisms underlying tumor development. Additionally, we will explore the evolving landscape of utilizing Eph receptors as potential targets for tumor therapy and diagnostic tools.
Assuntos
Neoplasias , Neovascularização Patológica , Receptores da Família Eph , Transdução de Sinais , Humanos , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/imunologia , Neovascularização Patológica/metabolismo , Receptores da Família Eph/metabolismo , Animais , Progressão da Doença , Imunidade , AngiogêneseRESUMO
BACKGROUND: Aortoesophageal fistula (AEF) is an extremely rare and highly fatal complication leading to a high risk of morbidity and mortality. Successful management of AEF after esophagectomy for esophageal carcinoma has rarely been reported in the literature. CASE PRESENTATION: Here we present a rare case of a 44-year-old female with complications of AEF after esophagectomy for esophageal carcinoma, mainly presented as vomiting of blood. Both computed tomographic and computed tomography angiography of the chest showed bilateral pleural effusion and atelectasis, while gastroscopy showed large gastrointestinal bleeding. Emergency surgery was performed that included the removal of the mediastinal abscess, left lower pulmonary wedge resection, and thoracic endovascular aortic repair (TEVAR), followed by supportive treatment. The surgery went successful, and the patient was followed up for 1 year after discharge and showed good recovery. We also reviewed previous literature on the history, causes, pathophysiology, clinical presentation, diagnosis, and treatment of AEF after esophagectomy for esophageal adenocarcinoma. CONCLUSIONS: In our case, thoracotomy combined with TEVAR was effective in treating AEF after esophagectomy for esophageal adenocarcinoma. This case provides successful experiences for clinical diagnosis and treatment of AEF after esophagectomy for esophageal carcinoma.
Assuntos
Adenocarcinoma , Doenças da Aorta , Carcinoma , Fístula Esofágica , Fístula Vascular , Adulto , Feminino , Humanos , Adenocarcinoma/cirurgia , Adenocarcinoma/complicações , Doenças da Aorta/cirurgia , Doenças da Aorta/complicações , Carcinoma/cirurgia , Correção Endovascular de Aneurisma , Fístula Esofágica/etiologia , Fístula Esofágica/cirurgia , Esofagectomia/efeitos adversos , Hemorragia Gastrointestinal , Fístula Vascular/etiologia , Fístula Vascular/cirurgiaRESUMO
Accurate pre-mRNA splicing is essential for proper protein translation; however, aberrant splicing is commonly observed in the context of cancer and genetic disorders. Notably, in genetic diseases, these splicing abnormalities often play a pivotal role. Substantial challenges persist in accurately identifying and classifying disease-induced aberrant splicing, as well as in development of targeted therapeutic strategies. In this review, we examine prevalent forms of aberrant splicing and explore potential therapeutic approaches aimed at addressing these splicing-related diseases. This summary contributes to a deeper understanding of the complexities about aberrant splicing and provide a foundation for the development of effective therapeutic interventions in the field of genetic disorders and cancer.
Assuntos
Processamento Alternativo , Neoplasias , Humanos , Splicing de RNA/genética , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Biossíntese de ProteínasRESUMO
Lung cancer's mortality is predominantly linked to post-chemotherapy recurrence, driven by the reactivation of dormant cancer cells. Despite the critical role of these reactivated cells in cancer recurrence and metastasis, the molecular mechanisms governing their therapeutic selection remain poorly understood. In this study, we conducted an integrative analysis by combining PacBio single molecule real-time (SMRT) sequencing with short reads Illumina RNA-seq. Our study revealed that cisplatin-induced dormant and reactivated cancer cells exhibited a noteworthy reduction in gene transcripts and alternative splicing events. Particularly, the differential alternative splicing events were found to be overlapping with the differentially expression genes and enriched in genes related to cell cycle and cell division. Utilizing ENCORI database and correlation analysis, we identified key splicing factors, including SRSF7, SRSF3, PRPF8, and HNRNPC, as well as RNA helicase such as EIF4A3, DDX39A, DDX11, and BRIP1, which were associated with the observed reduction in alternative splicing and subsequent decrease in gene expression. Our study demonstrated that lung cancer cells reduce gene transcripts through diminished alternative splicing events mediated by specific splicing factors and RNA helicase in response to the chemotherapeutic stress. These findings provide insights into the molecular mechanisms underlying the therapeutic selection and reactivation of dormant cancer cells. This discovery opens a potential avenue for the development of therapeutic strategies aimed at preventing cancer recurrence following chemotherapy.
RESUMO
EphB1 is implicated in numerous physiological and pathological processes, including nervous system diseases, cardiovascular diseases and cancers. It binds to membrane-bound ligands and drives bidirectional signaling. EphB1, along with its ligand ehrinB, plays a pivotal role in activating immune cells. However, despite its presence in dendritic cells (DCs), EphB1's involvement in the differentiation and maturation of DCs in cancers remains inadequately understood. In this study, we found compromised differentiation and maturation of DCs in EphB1-/- mice bearing lung adenocarcinoma syngeneic tumors. Our in vitro assays revealed that EphB1 phosphorylation induced DC differentiation and maturation. Cox-2, a key enzyme involved in the production of proinflammatory molecules, is implicated in DC differentiation induced by phosphorylated EphB1. Additionally, the study has identified lead compounds that specifically target EphB1 phosphorylation sites. Collectively, this research on EphB1 phosphorylation has provided valuable insights into the regulation of immune cell functionality and holds the potential for the development of innovative therapeutic strategies for a range of diseases.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Transdução de Sinais , Diferenciação Celular , Células DendríticasRESUMO
End-to-end scene text spotting has made significant progress due to its intrinsic synergy between text detection and recognition. Previous methods commonly regard manual annotations such as horizontal rectangles, rotated rectangles, quadrangles, and polygons as a prerequisite, which are much more expensive than using single-point. Our new framework, SPTS v2, allows us to train high-performing text-spotting models using a single-point annotation. SPTS v2 reserves the advantage of the auto-regressive Transformer with an Instance Assignment Decoder (IAD) through sequentially predicting the center points of all text instances inside the same predicting sequence, while with a Parallel Recognition Decoder (PRD) for text recognition in parallel, which significantly reduces the requirement of the length of the sequence. These two decoders share the same parameters and are interactively connected with a simple but effective information transmission process to pass the gradient and information. Comprehensive experiments on various existing benchmark datasets demonstrate the SPTS v2 can outperform previous state-of-the-art single-point text spotters with fewer parameters while achieving 19× faster inference speed. Within the context of our SPTS v2 framework, our experiments suggest a potential preference for single-point representation in scene text spotting when compared to other representations. Such an attempt provides a significant opportunity for scene text spotting applications beyond the realms of existing paradigms.
RESUMO
Purpose: With the adjustment of prevention strategies in December 2022, coronavirus disease 2019 (COVID-19) became widely prevalent in China. This study is aimed to describe the clinical characteristics of myasthenia gravis (MG) patients with COVID-19 and identify risk factors of exacerbation in MG patients with COVID-19 in Guangxi. Patients and Methods: A total of 489 MG patients and 587 control subjects in Guangxi during the COVID-19 pandemic were enrolled in this case-control study. After contacting the participants, the clinical data of MG patients and the control group were analyzed. The clinical characteristics of MG patients with COVID-19 were described. Multivariable logistic regression analysis was used for discovering independent risk factors of MG exacerbation in the patients with MG and COVID-19. Results: A total of 311 (75.30%) MG patients and 428 (72.91%) control subjects were infected with COVID-19, and 64.31% of MG patients with COVID-19 were women. The median age at the time of interview was 41 (IQR: 28, 54) years old, and median onset age was 36 (IQR: 24, 51), both of which were lower than those in MG patients without COVID-19. MG duration was 24 (IQR: 9, 72) months. About 44.69% of patients were generalized MG (GMG). About 11.90% of MG patients with COVID-19 showed severe COVID-19 symptoms and the duration of symptomatic COVID-19 was 9.57 ± 6.79 days, higher than those in the control group. About 35.69% MG patients with immunosuppressive drugs were infected with COVID-19, which is higher than those in the non-infected MG patients (21.57%). A total of 120 (38.59%) MG patients with COVID-19 had comorbidities. About 21 (20.19%) of the 104 MG patients without vaccination showed severe COVID-19 symptoms. Multivariable logistic regression analysis showed that baseline MG activities of daily living profile (MG-ADL, OR 1.280, 95% CI: 1.010-1.621, p = 0.041), duration of COVID-19 (OR 1.158, 95% CI: 1.100-1.220, p < 0.001), GMG (OR 2.331, 95% CI: 1.228, 4.426, p = 0.010), and lack of COVID vaccination (OR 2.075, 95% CI: 1.152, 3.738, p = 0.015) were independent factors of exacerbation in MG patients with COVID-19. Conclusion: MG patients with immunosuppressive drugs, younger onset, longer MG duration, or comorbidities are more susceptible to COVID-19. The baseline MG-ADL, duration of symptomatic COVID-19, GMG, and lack of COVID-19 vaccination are independent risk factors of exacerbation in MG patients with COVID-19.
RESUMO
This paper presents the inaugural character recognition competition for street view shop signs, including the associated tasks, datasets, participating teams, the winning team's solution, and justification for the award.
RESUMO
As the Human Microbiome Project (HMP) progresses, the relationship between microbes and human health has been receiving increasing attention. A growing number of reports support the correlation between cancer and microbes. However, most studies have focused on bacteria, rather than fungal communities. In this study, we studied the alteration in lung mycobiome in patients with non-small-cell lung cancer (NSCLC) using metagenomic sequencing and qPCR. The higher fungal diversity and more complex network were observed in the patients with NSCLC. In addition, Alternaria arborescens was found as the most relevant fungus to NSCLC, and the enrichment of it in cancerous tissue was also detected. This study proposes that the changes in fungal communities may be closely related to lung cancer, and provides insights into further exploration the relationship between lung cancer and fungi.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Micobioma , Humanos , Fungos/genética , PulmãoRESUMO
No definitive blood markers of DWI-FLAIR mismatch, a pivotal indicator of salvageable ischemic penumbra brain tissue, are known. We previously reported that CDC42 and RHOA are associated with the ischemic penumbra. Here, we investigated whether plasma CDC42 and RHOA are surrogate markers of DWI-FLAIR mismatch. Sixteen cynomolgus macaques (3 as controls and 13 for the stroke model) were included. Guided by digital subtraction angiography (DSA), a middle cerebral artery occlusion (MCAO) model was established by occluding the middle cerebral artery (MCA) with a balloon. MRI and neurological deficit scoring were performed to evaluate postinfarction changes. Plasma CDC42 and RHOA levels were measured by enzyme-linked immunosorbent assay (ELISA). The stroke model was successfully established in eight monkeys. Based on postinfarction MRI images, experimental animals were divided into a FLAIR (-) group (N = 4) and a FLAIR (+) group (N = 4). Plasma CDC42 in the FLAIR (-) group showed a significant decrease compared with that in the FLAIR (+) group (p < 0.05). No statistically significant difference was observed for plasma RHOA. The FLAIR (-) group showed a milder neurological function deficit and a smaller infarct volume than the FLAIR (+) group (p < 0.05). Therefore, plasma CDC42 might be a new surrogate marker for DWI-FLAIR mismatch.
RESUMO
BACKGROUND: To explore the possible carcinogenesis and help better diagnose and treat patients with synchronous multiple primary lung cancers (sMPLC), we systematically investigated the genetic and DNA methylation profiles of early-stage sMPLC and single primary lung cancer (SPLC) and explored the immune profiles in the tumor microenvironment. METHODS: Hundred and ninety-one patients with 191 nodules in the SPLC group and 132 patients with 295 nodules in the sMPLC group were enrolled. All the samples were subjected to wide panel-genomic sequencing. Genome-wide DNA methylation was assessed using the Infinium Human Methylation 850 K BeadChip. RNA-seq and CIBERSORT analyses were performed to identify the immune characteristics in these two groups. RESULTS: Lesions from sMPLC patients had lower TMB levels than that from SPLC patients. sMPLC had a similar genetic mutational landscape with SPLC, despite some subgroup genetic discrepancies. Distinct DNA methylation patterns were identified between the two groups. The differentially methylated genes were related to immune response pathways. RNA-seq analyses revealed more immune-related DEGs in sMPLC. Accordingly, more immune-related biological processes and pathways were identified in sMPLC. Aberrant DNA methylation was associated with the abnormal expression of immune-related genes. CIBERSORT analysis revealed the infiltration of immune cells was different between the two groups. CONCLUSION: Our study for the first time demonstrated genetic, epigenetic, and immune profile discrepancies between sMPLC and SPLC. Relative to the similar genetic mutational landscape, the DNA methylation patterns and related immune profiles were significantly different between sMPLC and SPLC, indicating their essential roles in the initiation and development of sMPLC.
Assuntos
Neoplasias Pulmonares , Neoplasias Primárias Múltiplas , Humanos , Metilação de DNA , Genoma , Mutação , Neoplasias Pulmonares/patologia , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Microambiente TumoralRESUMO
Lung cancer is the leading cause of cancer-related deaths worldwide. Tobacco smoking and air pollution are believed to be responsible for more than 90% of lung cancers. Respiratory pathogens are also known to be associated with the initiation and development of lung cancer. Despite the fact that the bacterial biomass in the lungs is lower than that in the intestinal tract, emerging evidence indicates that the lung is colonized by a diverse array of microbes. However, there is limited knowledge regarding the role of dysbiosis of the lung microbiota in the progression of lung cancer. In this review, we summarize the current information about the relationship between the microbiome and lung cancer. The objective is to provide an overview of the core composition of the microbiota in lung cancer as well as the role of specific dysbiosis of the lung microbiota in the progression of lung cancer and treatment of the disease.
RESUMO
Reactivation of chemotherapy-induced dormant cancer cells is the main cause of relapse and metastasis. The molecular mechanisms underlying remain to be elucidated. In this study, we introduced a cellular model that mimics the process of cisplatin responsiveness in NSCLC patients. We found that during the process of dormancy and reactivation induced by cisplatin, NSCLC cells underwent sequential EMT-MET with enrichment of cancer stem cells. The ATAC-seq combined with motif analysis revealed that OCT4-SOX2-TCF-NANOG motifs were associated with the enrichment of cancer stem cells induced by chemotherapy. Gene expression profiling suggested a dynamic regulatory mechanism during the process of enrichment of cancer stem cells, where Nanog showed upregulation in the dormant state and SOX2 showed upregulation in the reactivated state. Further, we showed that EphB1 and p-EphB1 showed dynamic expression in the process of cancer cell dormancy and reactivation, where the expression profiles of EphB1 and p-EphB1 showed negatively correlated. In the dormant EMT cells which showed disrupted cell-cell contacts, ligand-independent EphB1 promoted entry of lung cancer cells into dormancy through activating p-p38 and downregulating E-cadherin. On the contrary, in the state of MET, in which cell-cell adhesion was recovered, interactions of EphB1 and ligand EphrinB2 in trans promoted the stemness of cancer cells through upregulating Nanog and Sox2. In conclusion, lung cancer stem cells were enriched during the process of cellular response to chemotherapy. EphB1 cis- and trans- signalings function in the dormant and reactivated state of lung cancer cells respectively. It may provide a therapeutic strategy that target the evolution process of cancer cells induced by chemotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Ligantes , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Recidiva Local de Neoplasia , Células-Tronco Neoplásicas/metabolismo , Receptores Proteína Tirosina Quinases , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismoRESUMO
Ground-glass opacity (GGO)-associated pulmonary nodules have been known as a radiologic feature of early-stage lung cancers and exhibit an indolent biological behavior. However, the correlation between driver genes and radiologic features as well as the immune microenvironment remains poorly understood. We performed a custom 1021-gene panel sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients. A total of 130 multiple pulmonary nodules were sampled from 58 patients. Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry (IHC) and multiplex immunofluorescent staining (mIF) were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Compared with pure GGO nodules, mixed GGO nodules were enriched for invasive adenocarcinoma (IAC) (182/216 vs 73/118, P < .001). Eighty-eight percent (294/334) of GGO-associated nodules carried at least one mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway, and the alterations in these driver genes were mutually exclusive. The analysis of multifocal pulmonary nodules from the same patient revealed evidence of functional convergence on RTK/RAS pathways. Nodules with ERBB2/BRAF/MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations. IHC and mIF staining showed that KRAS-mutant GGO nodules displayed higher infiltration of CD4+ T cell and CD8+ T cell as well as stronger proliferation and immune inhibitory signals. Our study demonstrates a driver landscape of radiologically detectable GGO-associated pulmonary nodules in Chinese patients and supports that different driver patterns in RTK/RAS pathway are corresponding to different radiologic features.
Assuntos
Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Genômica , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/genética , Nódulos Pulmonares Múltiplos/patologia , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente TumoralRESUMO
Aortoesophageal fistula (AEF) caused by esophageal foreign body (EFB) ingestion is a life-threatening condition with a very low survival rate. However, the optimal management strategy remains undetermined. Here, we describe our successful management of a patient with AEF and mediastinitis. A 36-year-old man developed persistent chest and back pain and vomited fresh blood three days after removal of a pork bone in the esophagus under endoscopy in a local hospital. Computed tomography (CT) confirmed bilateral pulmonary infections, mediastinitis, and fistula of the aortic arch. After a multidiscipline discussion, a comprehensive staged strategy was made including salvaged thoracic endovascular aortic repair (TEVAR) to control fatal bleeding, adequate mediastinal debridement, drainage with cervical incision, and video-assisted thoracoscopic surgery, as well as jejunostomy to prevent nasal or gastrostomy reflux from aggravating the mediastinal infection. Furthermore, systematic personalized nutrition support and antibiotics were provided. The patient recovered well and has survived for 50 months until now. Careful assessment should be made with CT to ascertain the risk of AEF before and after the removal of EFB. A salvaged staged strategy of TEVAR with adequate mediastinal debridement and drainage in a less invasive approach may be a safer alternative for AEF patients with infections caused by EFB.
RESUMO
Background: Blepharospasm (BSP) and dry eye disease (DED) are clinically common diseases characterized by an increased blinking rate. A sustained eyelid muscle activity may alter the cortical sensorimotor concordance and lead to secondary functional changes. This study aimed to explore the central mechanism of BSP by assessing brain functional differences between the two groups and comparing them with healthy controls. Methods: In this study, 25 patients with BSP, 22 patients with DED, and 23 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The amplitude of low-frequency fluctuations (ALFF) was applied to analyze the imaging data. Results: Analysis of covariance (ANCOVA) revealed widespread differences in ALFF across the three groups. In comparison with healthy controls, patients with BSP showed abnormal ALFF in the sensorimotor integration related-brain regions, including the bilateral supplementary motor area (SMA), left cerebellar Crus I, left fusiform gyrus, bilateral superior medial prefrontal cortex (MPFC), and right superior frontal gyrus (SFG). In comparison with patients with DED, patients with BSP exhibited a significantly increased ALFF in the left cerebellar Crus I and left SMA. ALFF in the left fusiform gyrus/cerebellar Crus I was positively correlated with symptomatic severity of BSP. Conclusions: Our results reveal that the distinctive changes in the brain function in patients with BSP are different from those in patients with DED and healthy controls. The results further emphasize the primary role of sensorimotor integration in the pathophysiology of BSP.
RESUMO
Background: Increasing evidence from modern neuroimaging has confirmed that cervical dystonia (CD) is caused by network abnormalities. Specific brain networks are known to be crucial in patients suffering from CD. However, changes in network homogeneity (NH) in CD patients have not been characterized. Therefore, the purpose of this study was to investigate the NH of patients with CD. Methods: An automated NH method was used to analyze resting-state functional magnetic resonance (fMRI) data from 19 patients with CD and 21 gender- and age-matched healthy controls (HC). Correlation analysis were conducted between NH, illness duration and symptom severity measured by the Tsui scale. Results: Compared with the HC group, CD patients showed a lower NH in the right superior medial frontal gyrus. No significant correlations were found between abnormal NH values and illness duration or symptom severity. Conclusion: Our findings suggest the existence of abnormal NH in the default mode network (DMN) of CD patients, and thereby highlight the importance of the DMN in the pathophysiology of CD.
RESUMO
Cisplatin-based chemotherapy remains the standard care for non-small cell lung cancer (NSCLC) patients. Relapse after chemotherapy-induced dormancy affects the overall survival of patients. The evolution of cancer cells under chemotherapy stress is regulated by transcription factors (TFs) with binding sites initially buried deep within inaccessible chromatin. The transcription machinery and dynamic epigenetic alterations during the process of dormancy-reactivation of lung cancer cells after chemotherapy need to be investigated. Here, we investigated the chromatin accessibility of lung cancer cells after cisplatin treatment, using an assay for transposase-accessible chromatin sequencing (ATAC-seq). We observed that global chromatin accessibility was extensively improved. Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST) v.2 was used to elucidate TF-target interaction during the process of dormancy and reactivation. Enhancer regions and motifs specific to key TFs including JUN, MYC, SMAD3, E2F1, SP1, CTCF, SMAD4, STAT3, NFKB1, and KLF4 were enriched in differential loci ATAC-seq peaks of dormant and reactivated cancer cells induced by chemotherapy. The findings suggest that these key TFs regulated gene expressions during the process of dormancy and reactivation of cancer cells through altering promoter accessibility of target genes. Our study helps advance understanding of how cancer cells adapt to the stress induced by chemotherapy through TF binding motif accessibility.
RESUMO
BACKGROUND: Cisplatin-based chemotherapy is a therapeutic strategy against non-small cell lung cancer (NSCLC). However, cancers relapse after chemotherapy due to a dormant state of residual cancer cells. Extracellular vesicles and particles (EVPs) are active carriers of proteins and nucleic acid. Here, we aimed to study the molecular alterations and proteomic characteristics of EPV in dormant and reactivated cancer cells induced by cisplatin. METHODS: We used a short-term single dose of cisplatin to induce the dormant and reactivated cell status. We examined the gene expressional profiling and proteomic profiling of EVPs from dormant and reactivated cancer cells by RNA-sequencing and LC-MS/MS. RESULTS: We found substantial changes in gene expression and protein level in EVP. The genes with higher expression in dormant cancer cells were lipid transporter- and lipid metabolic-related genes. A total of 111 EVP proteins were upregulated in dormant cancer cells compared to those in control cells. Fifty differential expressed proteins (DEPs) were identified in EVPs from reactivated cancer cells compared to those in dormant cancer cells. Among the DEPs, we found that apolipoproteins such as APOA1 and APOE were significantly increased in dormant cancer cell-derived EVPs. Integration of EVP proteomes with transcriptional profiles of cancer cells revealed that the proteomic profiling of EVP derived from cancer cells can reflect the cellular status of cancer cells, which showed an activated lipid metabolism in dormant state. CONCLUSION: Lipoproteins enriched in EVPs reflect the activated lipid metabolism in dormant cancer cells and may provide potential biomarkers or therapeutic targets for cisplatin-based therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Proteômica , Células A549 , Antineoplásicos/farmacologia , Humanos , Mapas de Interação de ProteínasRESUMO
INTRODUCTION: Approximately 30% of patients diagnosed with stage Ia-b NSCLC die of recurrent disease after surgery. This study aimed to identify immune-related biomarkers that might predict tumor recurrence in stage Ia-b NSCLC within 40 months after curative resection. METHODS: Gene expression data of stage Ia-b NSCLC samples was retrieved from the TCGA database, the GEO databases, and the Second Xiangya hospital (XXEYY) database. 22 types of tumors infiltrating immune cells and the expression of immune-associated genes were investigated using CIBERSORT, immunohistochemical staining, and GSEA analyses in a total of 450 patients (80 in the training cohort and 370 in the validation cohorts). Recurrence-related immune features were selected based on the LASSO Cox regression model. RESULTS: High density of Tregs, Macrophages M0 and M1 cell could be observed in recurrence group while the memory B cell was more frequently enriched in controls, yet Tregs alone was significantly associated with tumor early recurrence in TCGA cohort, XYEYY cohort and GSE37745 dataset. A handful of immune-related genes were identified in the recurrence group. Based on Lasso regression analysis, the expressions of five immune-related genes, RLTPR, SLFN13, MIR4500HG, HYDIN and TPRG1 were closely correlated with tumor early recurrence. In the training cohort (TCGA), the combination of these five genes has sensitivity and specificity of 85% and 85%, with AUC of 0.91 (95% CI 0.84-0.98) for lung cancer early recurrence prediction, whereas in validation cohorts, the sensitivity and specificity using this panel was 61-89% and 54-82%, with AUC of 0.62-0.84. CONCLUSION: Our study demonstrated that the immune microenvironment signatures were closely related to tumor early recurrence. Compared to tumor-infiltrating lymphocytes, the expression of five immune-related genes could be robust biomarkers to predict early recurrence of stage Ia-b NSCLC after curative resection.