Yu Shi

Background. The tumor immune microenvironment (TIME) played an important role in immunotherapy prognosis and treatment response. Immune cells constitute a large part of the tumor microenvironment and regulate tumor progression. Our research is dedicated to studying the infiltrating immune cell in lung adenocarcinoma (LUAD) and seeking potential targets. Methods. The scRNA-seq data were collected from our FDZSH and two public datasets. The code for cell-type mapping algorithms was downloaded from the CIBERSORTx portal. The bioinformatics data of LUAD patients could be approached from The Cancer Genome Atlas (TCGA) portal. Weighted gene coexpression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analyses were performed to construct a risk model. TIMER2 and TIDE helped with the immune infiltration estimation, while PROGENy helped the cancer-related pathways enrichment analysis. GSE31210 dataset and IMVigor ICB therapy cohort validated our findings as the external validation datasets. Results. We clustered the scRNA-seq dataset (integrating our FDZSH datasets and other public datasets) into 23 subpopulations. After curated cell annotation, we implemented Cibersort and WGCNA analysis to anchor the brown module and natural killer cell cluster1 due to the most relationship with tumor trait. The overlap of the brown module gene, natural killer cell signature, and DEGs of tumor and adjacent normal samples was screened by LASSO Cox regression. The obtained 5-gene risk model showed an excellent prognostic performance in the validation dataset. Furthermore, there was a correlation between risk score and tumor-infiltrating immune cells and tumor genomics abnormity. Patients with higher risk scores had a significantly lower immunotherapy response rate. Conclusion. Our observations implied that immune cells played a pivotal role in TIME and established a 5-gene signature (including IDH2, ADRB2, SFTPC, CCDC69, and CCND2) on the basement of nature killer markers targeted by WGCNA analysis. The significance of clinical outcome and immunotherapy response prediction was validated robustly.

Background: Changes in glycometabolism of cancer cells provides cancer cells with growth advantages, which are also of great value in the prognosis prediction of the patients with lung adenocarcinoma. However, currently available studies are controversial. Methods: We successively collected 100 paired surgical specimens from patients with lung adenocarcinoma. The content of glycometabolic intermediates in tissues was tested by liquid chromatography-mass spectrometry. Follow-up was conducted every 6 months for patients enrolled in this study. Results: There were significant differences in the contents of six intermediates, including glucose (PConclusions: The contents of glucose, pyruvate, lactate, and citrate in cancer tissues are higher than that in para-carcinoma tissues, and the long-term survival decrease in patients with higher glucose, pyruvate, lactate, and citrate.

Background: Primary pure mucinous adenocarcinoma of the lung (PMA) is a rare subtype. However, correlations between clinicopathological features and genetic phenotypes with survival have not been described comprehensively.Methods: Pure mucinous adenocarcinoma patient information collected from the Surveillance, Epidemiology, and End Results (SEER) database, the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University (FDZSH), and the Cancer Genome Atlas (TCGA) were extracted, evaluated, and compared with other lung adenocarcinomas (LUAD) patient data. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to explore the functional importance of underlying molecular changes. Overall survival (OS) was evaluated with the Kaplan‐Meier method. Univariate and multivariate analysis through Cox proportional hazard regression identified risk factors that predicted OS, and the results were used to construct a nomogram to predict OS for PMA patients.Results: Overall, 3622 patients, 41 patients, and 15 patients with PMA were identified from the SEER, FDZSH, and TCGA databases, respectively. There were 345 differentially expressed genes, 30 differentially mutated genes and 72 differentially methylated genes were identified between PMA and other LUAD samples. In the SEER database, PMA had a better prognosis compared to other LUAD. Compared with patients with other LUAD, patients with PMA exhibited unique clinicopathological features, including fewer grade III/IV tumors, less pleural invasion, more early‐stage cancer, and more lower lobe carcinomas. Multivariate analyses showed that age, race, T stage, N stage, surgery, and chemotherapy were independent risk factors. The nomogram had a calibration index of 0.724.Conclusions: Our research identified unique clinicopathological characteristics and genetic phenotypes for PMA and other LUAD. The nomogram accurately predicted OS.

Immune infiltration may predict survival and have clinical significance in lung cancer. However, immune signatures derived from immune profiling based on bulk tumor transcriptomes have not been systematically established in lung adenocarcinoma. We aimed to construct an immune cell infiltrating score, using a new algorithm for evaluating immune infiltration, to improve the prognostic model of lung adenocarcinoma. Public datasets of lung adenocarcinoma from the Gene Expression Omnibus and The Cancer Genome Atlas were adopted as the training and validation cohorts. Fractions of different immune cell subtypes in each sample were estimated using the CIBERSORT algorithm. The immune infiltrating score was further developed by a least absolute shrinkage and selection operator regression model. The prognostic value and clinical relationship of the model was then further explored. An immune infiltrating score model was established on the basis of the immune cells in the training cohort. A high score was associated with significantly worse survival in patients with lung adenocarcinoma (P < 0.001). The prognostic value of the score was confirmed in the validation cohort. The immune infiltrating score could improve the accuracy of predictions of survival when combined with the staging system. Furthermore, the score was potentially associated with patient smoking status and histologic subtype of lung adenocarcinoma. Its possible association with the efficacy of adjuvant chemotherapy was not statistically significant. The immune cell infiltrating score has prognostic significance in predicting overall survival in patients with lung adenocarcinoma.

OBJECTIVES A small pulmonary granuloma (SPG) is often misdiagnosed as lung cancer in diabetic patients by positron emission tomography/computed tomography (PET/CT). The present study was conducted to investigate whether diabetes is the influencing factor and to determine other related factors that have an impact on the diagnostic results following PET/CT examination. METHODS All clinical, imaging and pathological data of patients diagnosed with pulmonary nodules by PET/CT from January 2004 to December 2017 in our department were collected. Patients with an SPG who were wrongly diagnosed with lung cancer by PET/CT were enrolled (n=79). The propensity score matching method was used to create a comparable control adenocarcinoma group (n=395). Maximum standard uptake values, diabetes and fasting blood-glucose (FBG) were determined and analysed. RESULTS The average maximum standard uptake values in the 2 groups were comparable (P=0.801). Maximum standard uptake values in 5 subsections were not significantly different between the 2 groups (P=0.135). The odds ratio (OR) of 3.326 [95% confidence interval (CI) 1.671-6.623] for diabetes favoured misdiagnosis and was statistically significant (P<0.001). Furthermore, in patients with high FBG levels (7.0mmol/l), the risk of misdiagnosis of SPG increased significantly compared with normal FBG level (OR 2.601, 95% CI 1.174-5.761; P=0.015). CONCLUSIONS Diabetes and high FBG level were the influencing factors in the false-positive results of lung cancer by PET/CT examination.

Ku80 is an important DNA repair protein. Here, this study sought to investigate clinical impacts of Ku80 expression for patients with superficial esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis of Ku80 expression was carried out in normal esophageal mucosa, squamous epithelial dysplasia, carcinoma in situ, and superficial ESCC. Its relationships with clinicopathological features and survival of superficial ESCC patients were further clarified. Lentivirus‐mediated RNA interference was used to silence Ku80 gene in ECA109 and KYSE150 cells. Both quantitative real‐time PCR and Western blot were employed to evaluate Ku80 levels. CCK‐8 assay, clone formation assay, flow cytometry, and tumorigenesis experiment were performed to evaluate the malignant phenotype of ECA109 and KYSE150 cells. Increased Ku80 expression was observed in dysplastic esophageal mucosa and carcinoma in situ compared to normal esophageal mucosa (P < 0.001, P < 0.001). Ku80 expression was further increased in superficial ESCC in comparison with dysplastic esophageal mucosa and carcinoma in situ (P < 0.001, P = 0.034). In superficial ESCC, Ku80 overexpression was related to tumor differentiation (P = 0.017), T status (P = 0.011), nodal involvement (P = 0.005), TNM stage (P = 0.004), and postoperative recurrence (P = 0.008). Cox proportional hazards regression showed tumor differentiation, T status, nodal involvement, TNM stage, and Ku80 expression were both independent predictors of patients’ overall survival and disease‐free survival. Ku80 shRNA effectively reduced Ku80 expression, which significantly inhibited proliferation, clone formation, and induced apoptosis in ECA109 and KYSE150 cells. The tumor growth of xenografts was significantly reduced by Ku80 silencing in ECA109 and KYSE150 cells. Ku80 overexpression associates with unfavorable prognosis of superficial ESCC patients, and silencing of Ku80 could inhibit the malignant behavior of ESCC cells. We provide evidence that Ku80 has unrecognized roles in carcinogenesis and development of ESCC.

TRPCs have been demonstrated to be widely expressed in different cancers. In recent years, a number of studies closely investigated the roles of TRPCs in cancer cells. Most of the results show that both mRNA and protein levels of TRPCs significantly increase in cancer tissues compared with healthy controls. TRPCs regulate Ca²⁺ homeostasis, contribute to cell cycle regulation and the expression/activation of Ca²⁺-related factors, and thus play critical roles in the proliferation of cancer cells. Therefore, TRPCs could act as potential drug targets for cancer diagnosis and therapy.

Purpose Video-assisted thoracoscopic surgery (VATS) is widely used in thoracic surgery and increasingly applied to pulmonary metastasectomy. The purpose of this study was to identify prognostic factors of patients undergoing VATS pulmonary metastasectomy from colorectal cancer (CRC). Methods Between January 2005 and June 2015, a total of 154 patients underwent VATS pulmonary metastasectomy from CRC. Patient demographic data and characteristics of the primary tumor and pulmonary metastasis were analyzed to identify factors significantly correlated with prognosis. Results The median follow-up period after pulmonary resection was 37 months. The cumulative 5-year overall survival rate after VATS pulmonary metastasectomy from CRC was 71.3%. History of metastasis to other sites (p = 0.035), status of mediastinal lymph nodes (p < 0.001), and preoperative carcinoembryonic antigen (CEA) level (p = 0.013) were identified as independent prognostic factors. Subgroup analysis with a combination of these three independent prognostic factors revealed 5-year OS rates of 91.0, 70.0, 30.3, and 0.0% for patients with zero, one, two, and three risk factors, respectively. Other factors, such as sex, disease-free interval, T stage of primary tumor, and status of lymph node near the primary tumor, were not significantly associated with prognosis. Conclusion VATS pulmonary metastasectomy is efficacious for patients with CRC pulmonary metastases. History of metastasis to other sites, status of mediastinal lymph nodes, and preoperative CEA level were identified as independent prognostic factors. The number of risk factors significantly influenced patient survival.

The present study aimed to explore gene and microRNA (miRNA) expression differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified by analyzing mRNA and miRNA expression data in normal and cancerous lung tissues that were obtained from The Cancer Genome Atlas database. A total of 778 DEGs and 7 DEMs were identified. Altered gene functions and signaling pathways were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, which revealed that DEGs were significantly enriched in extracellular matrix organization, cell differentiation, negative regulation of toll signaling pathway, and several other terms and pathways. Transcription factor (TF)‑miRNA‑gene networks in LUAD and LUSC were predicted using the TargetScan, Miranda, and TRANSFAC databases, which revealed the regulatory links among the TFs, DEMs, and DEGs. The central TFs, i.e., the TFs in the middle of the TF‑miRNA‑gene network, of LUAD and LUSC were similar. Although LUAD and LUSC shared similar miRNAs in the predicted networks, miR‑29b‑3p was demonstrated to be upregulated only in LUAD, whereas miR‑1, miR‑105‑5p, and miR‑193b‑5p were altered in LUSC. These findings may improve our understanding of the different molecular mechanisms in non‑small cell lung cancers and may promote new and accurate strategies for prevention, diagnosis, and treatment.