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1.
Ann Transl Med ; 9(16): 1354, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34532491

RESUMO

Osimertinib has efficacy superior to that of standard epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance. MET missense mutations have been demonstrated to mediate resistance to MET-TKIs, such as crizotinib. But the role of MET missense mutations in mediating EGFR TKI resistance is undefined. With the increasing use of next-generation sequencing (NGS) at diagnosis, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Herein, we report the first case of MET D1228N mutation mediating acquired resistance to osimertinib in a MET TKI-naïve NSCLC. The patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion initially responded to osimertinib with progression-free survival (PFS) lasting 11 months and then developed resistance with an acquired mutation of MET D1228N. Subsequently, combination therapy of cabozantinib and osimertinib was administrated to the patient, and her clinical symptoms were rapidly relieved within one week with good tolerance. She remained on the combined treatment for 10 months. Finally, she achieved an overall survival (OS) of 25 months. Based on our findings, patient with MET D1228N mutant lung adenocarcinoma clinically benefited from combinatorial therapy of cabozantinib and osimertinib after osimertinib resistance.

2.
Mol Diagn Ther ; 25(4): 487-494, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34133003

RESUMO

BACKGROUND: Precise detection of anaplastic lymphoma kinase (ALK) rearrangement guides the application of ALK-targeted tyrosine kinase inhibitors (ALK-TKIs) in patients with non-small-cell lung cancer (NSCLC). Next-generation sequencing (NGS) has been widely used in clinics, but DNA-based NGS used to detect fusion genes has delivered false-negative results. However, fusion genes can be successfully detected at the transcription level and with higher sensitivity using RNA-based reverse transcription polymerase chain reaction (RT-PCR). OBJECTIVE: This study compared the performance of RT-PCR and NGS in the detection of echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion in Chinese patients with NSCLC. METHODS: Formalin-fixed paraffin-embedded tissues from 153 patients who were pathologically diagnosed as having NSCLC were collected from November 2017 to October 2019. Both DNA/RNA-based NGS and RNA-based RT-PCR were used to detect EML4-ALK fusion. For samples with discordant ALK status results, fluorescence in situ hybridization (FISH) or Sanger sequencing was used to further confirm the ALK status. RESULTS: In total, 124 samples were successfully analyzed using both NGS and RT-PCR. For 118 samples, results were consistent between NGS and RT-PCR, with 25 reported as ALK fusion positive and 93 as ALK fusion negative, achieving a concordance rate of 95.16%. Among the six samples with disconcordant results, five were positive using RT-PCR but negative using NGS, and one was positive using NGS but negative using RT-PCR. Four of six cases with disconcordant results (three RT-PCR positive and one NGS positive) were successfully validated using either FISH or Sanger sequencing. CONCLUSIONS: Compared with NGS, RT-PCR appears to be a reliable method of detecting EML4-ALK fusion in patients with NSCLC.

3.
Front Oncol ; 11: 631964, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34026611

RESUMO

Background: Myasthenia gravis (MG) is the most common paraneoplastic syndromes of thymoma and closely related to thymus abnormalities. Timely detecting of the risk of MG would benefit clinical management and treatment decision for patients with thymoma. Herein, we developed a 3D DenseNet deep learning (DL) model based on preoperative computed tomography (CT) as a non-invasive method to detect MG in thymoma patients. Methods: A large cohort of 230 thymoma patients in a hospital affiliated with a medical school were enrolled. 182 thymoma patients (81 with MG, 101 without MG) were used for training and model building. 48 cases from another hospital were used for external validation. A 3D-DenseNet-DL model and five radiomic models were performed to detect MG in thymoma patients. A comprehensive analysis by integrating machine learning and semantic CT image features, named 3D-DenseNet-DL-based multi-model, was also performed to establish a more effective prediction model. Findings: By elaborately comparing the prediction efficacy, the 3D-DenseNet-DL effectively identified MG patients and was superior to other five radiomic models, with a mean area under ROC curve (AUC), accuracy, sensitivity, and specificity of 0.734, 0.724, 0.787, and 0.672, respectively. The effectiveness of the 3D-DenseNet-DL-based multi-model was further improved as evidenced by the following metrics: AUC 0.766, accuracy 0.790, sensitivity 0.739, and specificity 0.801. External verification results confirmed the feasibility of this DL-based multi-model with metrics: AUC 0.730, accuracy 0.732, sensitivity 0.700, and specificity 0.690, respectively. Interpretation: Our 3D-DenseNet-DL model can effectively detect MG in patients with thymoma based on preoperative CT imaging. This model may serve as a supplement to the conventional diagnostic criteria for identifying thymoma associated MG.

4.
Ann Transl Med ; 9(7): 545, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33987243

RESUMO

Background: Epidermal growth factor receptor (EGFR) co-mutated with TP53 could reduce responsiveness to tyrosine kinase inhibitors (TKIs) and worsen patients' prognosis compared to TP53 wild type patients in. EGFR: mutated lung adenocarcinomas (LUAD). To identify this genetically unique subset prior to treatment through computed tomography (CT) images had not been reported yet. Methods: Stage III and IV LUAD with known mutation status of EGFR and TP53 from The First Affiliated Hospital of Sun Yat-sen University (May 1, 2017 to June 1, 2020) were collected. Characteristics of pretreatment enhanced-CT images were analyzed. One-versus-one was used as the multiclass classification strategy to distinguish the three subtypes of co-mutations: EGFR + & TP53 +, EGFR + & TP53 -, EGFR -. The clinical model, semantic model, radiomics model and integrated model were built. Area under the receiver-operating characteristic curves (AUCs) were used to evaluate the prediction efficacy. Results: A total of 199 patients were enrolled, including 83 (42%) cases of EGFR -, 55 (28%) cases of EGFR + & TP53 +, 61 (31%) cases of EGFR + & TP53 -. Among the four different models, the integrated model displayed the best performance for all the three subtypes of co-mutations: EGFR - (AUC, 0.857; accuracy, 0.817; sensitivity, 0.998; specificity, 0.663), EGFR + & TP53 + (AUC, 0.791; accuracy, 0.758; sensitivity, 0.762; specificity, 0.783), EGFR + & TP53 - (AUC, 0.761; accuracy, 0.813; sensitivity, 0.594; specificity, 0.977). The radiomics model was slightly inferior to the integrated model. The results for the clinical and the semantic models were dissatisfactory, with AUCs less than 0.700 for all the three subtypes. Conclusions: CT imaging based artificial intelligence (AI) is expected to distinguish co-mutation status involving TP53 and EGFR. The proposed integrated model may serve as an important alternative marker for preselecting patients who will be adaptable to and sensitive to TKIs.

5.
Ann Surg Oncol ; 28(11): 6747-6757, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33751300

RESUMO

BACKGROUND: The aim of this work is to explore the impact of the number of sampling sites (NuSS) and sampling location on microvascular invasion (MVI) detection rate and long-term survival of hepatocellular carcinoma (HCC), and determine the minimum NuSS for sufficient MVI detection. PATIENTS AND METHODS: From January 2008 to March 2017, 1144 HCC patients who underwent hepatectomy were retrospectively enrolled. Associations between NuSS and MVI positive rates and overall survival were investigated. NuSS thresholds were determined by Chow test and confirmed prospectively in 305 patients from April 2017 to February 2019. In the prospective cohort, the distribution of MVI in different sampling locations and its prognostic effect was evaluated. RESULTS: MVI positive rates increased as NuSS increased, steadily reaching a plateau when NuSS reached a threshold. A threshold of four, six, eight, and eight sampling sites within paracancerous parenchyma ≤ 1 cm from tumor was required for detecting MVI in solitary tumors measuring 1.0-3.0, 3.1-4.9, and ≥ 5.0 cm and multiple tumors. Patients with adequate NuSS achieved longer survival than those with inadequate NuSS [hazard ratio (HR) = 0.75, P = 0.043]. For all MVI-positive patients, MVI could be detected positive in paracancerous parenchyma ≤ 1 cm from tumor. Patients with MVI positive in paracancerous parenchyma > 1 cm had higher recurrence risk than those with MVI positive only in parenchyma ≤ 1 cm (HR = 6.05, P < 0.001). CONCLUSIONS: Adequate NuSS is associated with higher MVI detection rate and better survival of HCC patients. We recommend four, six, eight, and eight as the cut-points for evaluating MVI sampling quality and patients' prognostic stratification in the subgroups of solitary tumors measuring 1.0-3.0 cm, 3.1-4.9 cm and ≥ 5.0 cm and multiple tumors, respectively.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Humanos , Neoplasias Hepáticas/cirurgia , Microvasos , Invasividade Neoplásica , Recidiva Local de Neoplasia/cirurgia , Estudos Prospectivos , Estudos Retrospectivos
6.
BMC Med ; 19(1): 80, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33775248

RESUMO

BACKGROUND: Targeted therapy and immunotherapy put forward higher demands for accurate lung cancer classification, as well as benign versus malignant disease discrimination. Digital whole slide images (WSIs) witnessed the transition from traditional histopathology to computational approaches, arousing a hype of deep learning methods for histopathological analysis. We aimed at exploring the potential of deep learning models in the identification of lung cancer subtypes and cancer mimics from WSIs. METHODS: We initially obtained 741 WSIs from the First Affiliated Hospital of Sun Yat-sen University (SYSUFH) for the deep learning model development, optimization, and verification. Additional 318 WSIs from SYSUFH, 212 from Shenzhen People's Hospital, and 422 from The Cancer Genome Atlas were further collected for multi-centre verification. EfficientNet-B5- and ResNet-50-based deep learning methods were developed and compared using the metrics of recall, precision, F1-score, and areas under the curve (AUCs). A threshold-based tumour-first aggregation approach was proposed and implemented for the label inferencing of WSIs with complex tissue components. Four pathologists of different levels from SYSUFH reviewed all the testing slides blindly, and the diagnosing results were used for quantitative comparisons with the best performing deep learning model. RESULTS: We developed the first deep learning-based six-type classifier for histopathological WSI classification of lung adenocarcinoma, lung squamous cell carcinoma, small cell lung carcinoma, pulmonary tuberculosis, organizing pneumonia, and normal lung. The EfficientNet-B5-based model outperformed ResNet-50 and was selected as the backbone in the classifier. Tested on 1067 slides from four cohorts of different medical centres, AUCs of 0.970, 0.918, 0.963, and 0.978 were achieved, respectively. The classifier achieved high consistence to the ground truth and attending pathologists with high intraclass correlation coefficients over 0.873. CONCLUSIONS: Multi-cohort testing demonstrated our six-type classifier achieved consistent and comparable performance to experienced pathologists and gained advantages over other existing computational methods. The visualization of prediction heatmap improved the model interpretability intuitively. The classifier with the threshold-based tumour-first label inferencing method exhibited excellent accuracy and feasibility in classifying lung cancers and confused nonneoplastic tissues, indicating that deep learning can resolve complex multi-class tissue classification that conforms to real-world histopathological scenarios.


Assuntos
Aprendizado Profundo , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Estudos Retrospectivos
7.
Ann Surg ; 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33630430

RESUMO

OBJECTIVE: To investigate the effectiveness of a circulating tumor cell (CTC)-based classifier in stratifying stage IB lung adenocarcinoma (LUAD). SUMMARY BACKGROUND DATA: Stage IB LUADs have an approximately 70% 5-year survival rate. The clinical application of adjuvant chemotherapy (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: 212 stage IB LUAD patients were enrolled and were divided into three 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 (PFS, P < 0.0001) and overall survival (OS, P < 0.0001) than patients with < 4 CTCs. CTC number remained the strongest predictor of PFS and OS 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 two 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.

9.
Mol Cancer ; 19(1): 147, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032611

RESUMO

BACKGROUND: The highly intra-tumoral heterogeneity and complex cell origination of prostate cancer greatly limits the utility of traditional bulk RNA sequencing in finding better biomarker for disease diagnosis and stratification. Tissue specimens based single-cell RNA sequencing holds great promise for identification of novel biomarkers. However, this technique has yet been used in the study of prostate cancer heterogeneity. METHODS: Cell types and the corresponding marker genes were identified by single-cell RNA sequencing. Malignant states of different clusters were evaluated by copy number variation analysis and differentially expressed genes of pseudo-bulks sequencing. Diagnosis and stratification of prostate cancer was estimated by receiver operating characteristic curves of marker genes. Expression characteristics of marker genes were verified by immunostaining. RESULTS: Fifteen cell groups including three luminal clusters with different expression profiles were identified in prostate cancer tissues. The luminal cluster with the highest copy number variation level and marker genes enriched in prostate cancer-related metabolic processes was considered the malignant cluster. This cluster contained a distinct subgroup with high expression level of prostate cancer biomarkers and a strong distinguishing ability of normal and cancerous prostates across different pathology grading. In addition, we identified another marker gene, Hepsin (HPN), with a 0.930 area under the curve score distinguishing normal tissue from prostate cancer lesion. This finding was further validated by immunostaining of HPN in prostate cancer tissue array. CONCLUSION: Our findings provide a valuable resource for interpreting tumor heterogeneity in prostate cancer, and a novel candidate marker for prostate cancer management.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/classificação , Neoplasias da Próstata/patologia , Análise de Célula Única/métodos , Humanos , Masculino , Prognóstico , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Curva ROC , Taxa de Sobrevida
10.
Sci Adv ; 6(43)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33097539

RESUMO

Leveraging the endogenous homology-directed repair (HDR) pathway, the CRISPR-Cas9 gene-editing system can be applied to knock in a therapeutic gene at a designated site in the genome, offering a general therapeutic solution for treating genetic diseases such as hemoglobinopathies. Here, a combined supramolecular nanoparticle (SMNP)/supramolecular nanosubstrate-mediated delivery (SNSMD) strategy is used to facilitate CRISPR-Cas9 knockin of the hemoglobin beta (HBB) gene into the adeno-associated virus integration site 1 (AAVS1) safe-harbor site of an engineered K562 3.21 cell line harboring the sickle cell disease mutation. Through stepwise treatments of the two SMNP vectors encapsulating a Cas9•single-guide RNA (sgRNA) complex and an HBB/green fluorescent protein (GFP)-encoding plasmid, CRISPR-Cas9 knockin was successfully achieved via HDR. Last, the HBB/GFP-knockin K562 3.21 cells were introduced into mice via intraperitoneal injection to show their in vivo proliferative potential. This proof-of-concept demonstration paves the way for general gene therapeutic solutions for treating hemoglobinopathies.

11.
Pharmacol Ther ; 216: 107672, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32910933

RESUMO

Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been commonly used for the treatment and prevention of malaria, and the treatment of autoimmune diseases for several decades. As their new mechanisms of actions are identified in recent years, CQ and HCQ have wider therapeutic applications, one of which is to treat viral infectious diseases. Since the pandemic of the coronavirus disease 2019 (COVID-19), CQ and HCQ have been subjected to a number of in vitro and in vivo tests, and their therapeutic prospects for COVID-19 have been proposed. In this article, the applications and mechanisms of action of CQ and HCQ in their conventional fields of anti-malaria and anti-rheumatism, as well as their repurposing prospects in anti-virus are reviewed. The current trials and future potential of CQ and HCQ in combating COVID-19 are discussed.


Assuntos
Antimaláricos/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Antimaláricos/farmacocinética , Antirreumáticos/farmacocinética , Antivirais/farmacocinética , COVID-19 , Cloroquina/farmacocinética , Infecções por Coronavirus/metabolismo , Reposicionamento de Medicamentos , Humanos , Malária/tratamento farmacológico , Pandemias , Pneumonia Viral/metabolismo , SARS-CoV-2
12.
Ann Transl Med ; 8(15): 930, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32953730

RESUMO

Background: Programmed death ligand-1 (PD-L1) expression remains a crucial predictor in selecting patients for immunotherapy. The current study aimed to non-invasively predict PD-L1 expression based on chest computed tomography (CT) images in advanced lung adenocarcinomas (LUAD), thus help select optimal patients who can potentially benefit from immunotherapy. Methods: A total of 127 patients with stage III and IV LUAD were enrolled into this study. Pretreatment enhanced thin-section CT images were available for all patients and were analyzed in terms of both morphologic characteristics by radiologists and deep learning (DL), so to further determine the association between CT features and PD-L1 expression status. Univariate analysis and multivariate logical regression analysis were applied to evaluate significant variables. For DL, the 3D DenseNet model was built and validated. The study cohort were grouped by PD-L1 Tumor Proportion Scores (TPS) cutoff value of 1% (positive/negative expression) and 50% respectively. Results: Among 127 LUAD patients, 46 (36.2%) patients were PD-L1-positive and 38 (29.9%) patients expressed PD-L1-TPS ≥50%. For morphologic characteristics, univariate and multivariate analysis revealed that only lung metastasis was significantly associated with PD-L1 expression status despite of different PD-L1 TPS cutoff values, and its Area under the receiver operating characteristic curve (AUC) for predicting PD-L1 expression were less than 0.700. On the other hand, the predictive value of DL-3D DenseNet model was higher than that of the morphologic characteristics, with AUC more than 0.750. Conclusions: The traditional morphologic CT characteristics analyzed by radiologists show limited prediction efficacy for PD-L1 expression. By contrast, CT-derived deep neural network improves the prediction efficacy, it may serve as an important alternative marker for clinical PD-L1 detection.

14.
Theranostics ; 10(6): 2553-2570, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194819

RESUMO

Rationale: Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated. Methods: miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo. Results: MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1ɑ was identified as the transcription mediator of miR-1275. Activation of Wnt/ß-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/ß-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/ß-catenin and Notch pathways, including DKK3, SFRP1, GSK3ß, RUNX3, and NUMB, respectively, which resulted in signaling activation. Conclusions: Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/ß-catenin and Notch signaling pathways. Thus, HIF-1ɑ-regulated miR-1275 might be a potential therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , MicroRNAs/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Fenótipo , Receptores Notch/genética , Receptores Notch/metabolismo , Regulação para Cima , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
17.
Cancer Immunol Res ; 8(4): 479-492, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32075801

RESUMO

The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69+CD103+ Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell-T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells in vitro and in vivo. PD-L1 blockade unleashed Trm cells specifically in the patient-derived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevity of Trm cells and enhance antitumor immunity in gastric adenocarcinoma.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ácidos Graxos/química , Memória Imunológica , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Microambiente Tumoral , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antígenos CD/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Humanos , Cadeias alfa de Integrinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Células Neoplásicas Circulantes/imunologia , Oxirredução , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
18.
ACS Appl Mater Interfaces ; 12(5): 5671-5679, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31940177

RESUMO

Dynamically monitoring the clonal evolution of lung cancer and performing molecular analyses on tumor cells are challenging but necessary tasks to adjust therapeutic interventions and evaluate treatment efficacy. Circulating tumor cells (CTCs), as a "liquid biopsy", may offer an auxiliary tool to identify phenotypic transformation of solid tumors at primary or metastatic sites and uncover their corresponding molecular variation. Herein, we developed an aptamer-modified PEG-PLGA-nanofiber (PPN) microfluidic system optimized for recognizing rare CTC subtypes in lung cancer patients. This unique purification system can be adopted to monitor the clonal evolution of solid tumors by following the intrinsic immunophenotypes of CTCs, while significantly enhancing capture efficiency for polyclonal-derived tumor cells, further facilitating therapeutic evaluation via dynamic CTC enumeration. Combining with downstream single-cell sequencing, the aptamer-modified-PPN microfluidic system was able to provide early insight into tumor heterogeneity and predict histologic transformation in advance, broadening its clinical applications in lung cancer patients.


Assuntos
Aptâmeros de Nucleotídeos/genética , Evolução Clonal/genética , Neoplasias Pulmonares , Nanofibras/química , Células Neoplásicas Circulantes/patologia , Animais , Linhagem Celular Tumoral , Humanos , Biópsia Líquida/instrumentação , Biópsia Líquida/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Poliésteres/química , Polietilenoglicóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int Immunopharmacol ; 80: 106198, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31954274

RESUMO

The interaction between CD155 and its high-affinity ligand TIGIT is being increasingly investigated in various solid tumors. However, the prognostic significance of CD155 and TIGIT in lung adenocarcinoma (LUAD) remains unclear. In this study, immunohistochemistry was applied in 334 LUAD cases to evaluate the expression of CD155 and TIGIT. Western blotting was conducted in 5 paired primary LUAD and adjacent normal lung tissues. Our results reveal that CD155 and TIGIT are overexpressed in LUAD tissues and that aberrant overexpression is closely correlated with poor clinical outcomes (P < 0.01). The multivariate model also shows that CD155 expression is an independent risk factor for LUAD (RR, 1.34; P = 0.036). Moreover, patients expressing high CD155 and TIGIT simultaneously presented shorter overall survival (OS) (P < 0.01) and progression-free survival (PFS) (P < 0.01). These findings suggest that CD155 and TIGIT can make up a prognosticating tool to predict clinical outcomes, thereby contributing to personalized medical care in LUAD.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores Imunológicos/metabolismo , Receptores Virais/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Pulmão/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
20.
FASEB J ; 34(3): 4384-4402, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31961020

RESUMO

Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.


Assuntos
Intestinos/patologia , Macrófagos do Fígado/metabolismo , Fígado/metabolismo , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/metabolismo , Animais , Western Blotting , Polaridade Celular/fisiologia , Citometria de Fluxo , Imunofluorescência , Proteína HMGB1/sangue , Hepatócitos/metabolismo , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Marcação In Situ das Extremidades Cortadas , Inflamação/sangue , Inflamação/metabolismo , Lipopolissacarídeos/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/mortalidade , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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