Construction of a Prognostic Prediction Model of Patients with Pathologic N0 in Resected Invasive Mucinous Adenocarcinoma of the Lung / 中国肺癌杂志

BACKGROUND@#Invasive mucinous adenocarcinoma (IMA) was a rare and specific type of lung adenocarcinoma, which was often characterized by fewer lymphatic metastases. Therefore, it was difficult to evaluate the prognosis of these tumors based on the existing tumor-node-metastasis (TNM) staging. So, this study aimed to develop Nomograms to predict outcomes of patients with pathologic N0 in resected IMA.@*METHODS@#According to the inclusion criteria and exclusion criteria, IMA patients with pathologic N0 in The Affiliated Lihuili Hospital of Ningbo University (training cohort, n=78) and Ningbo No.2 Hospital (validation cohort, n=66) were reviewed between July 2012 and May 2017. The prognostic value of the clinicopathological features in the training cohort was analyzed and prognostic prediction models were established, and the performances of models were evaluated. Finally, the validation cohort data was put in for external validation.@*RESULTS@#Univariate analysis showed that pneumonic type, larger tumor size, mixed mucinous/non-mucinous component, and higher overall stage were significant influence factors of 5-year progression-free survival (PFS) and overall survival (OS). Multivariate analysis further indicated that type of imaging, tumor size, mucinous component were the independent prognostic factors for poor 5-year PFS and OS. Moreover, the 5-year PFS and OS rates were 62.82% and 75.64%, respectively. In subgroups, the survival analysis also showed that the pneumonic type and mixed mucinous/non-mucinous patients had significantly poorer 5-year PFS and OS compared with solitary type and pure mucinous patients, respectively. The C-index of Nomograms with 5-year PFS and OS were 0.815 (95%CI: 0.741-0.889) and 0.767 (95%CI: 0.669-0.865). The calibration curve and decision curve analysis (DCA) of both models showed good predictive performances in both cohorts.@*CONCLUSIONS@#The Nomograms based on clinicopathological characteristics in a certain extent, can be used as an effective prognostic tool for patients with pathologic N0 after IMA resection.

Identification and Analysis of SND1 as an Oncogene and Prognostic Biomarker for Lung Adenocarcinoma / 中国肺癌杂志

BACKGROUND@#Transcription factor (TF) can bind specific sequences that either promotes or represses the transcription of target genes, and exerts important effects on tumorigenesis, migration, invasion. Staphylococcal nuclease-containing structural domain 1 (SND1), which is a transcriptional co-activator, is considered as a promising target for tumor therapy. However, its role in lung adenocarcinoma (LUAD) remains unclear. This study aims to explore the role of SND1 in LUAD.@*METHODS@#Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) database was obtained to explore the association between SND1 and the prognosis, as well as the immune cell infiltration, and subcellular localization in LUAD tissues. Furthermore, the functional role of SND1 in LUAD was verified in vitro. EdU assay, CCK-8 assay, flow cytometry, scratch assay, Transwell assay and Western blot were performed.@*RESULTS@#SND1 was found to be upregulated and high expression of SND1 is correlated with poor prognosis of LUAD patients. In addition, SND1 was predominantly present in the cytoplasm of LUAD cells. Enrichment analysis showed that SND1 was closely associated with the cell cycle, as well as DNA replication, and chromosome segregation. Immune infiltration analysis showed that SND1 was closely associated with various immune cell populations, including T cells, B cells, cytotoxic cells and dendritic cells. In vitro studies demonstrated that silencing of SND1 inhibited cell proliferation, invasion and migration of LUAD cells. Besides, cell cycle was blocked at G1 phase by down-regulating SND1.@*CONCLUSIONS@#SND1 might be an important prognostic biomarker of LUAD and may promote LUAD cells proliferation and migration.

TRIP13 Enhances Radioresistance of Lung Adenocarcinoma Cells through the Homologous Recombination Pathway / 中国肺癌杂志

BACKGROUND@#Radiation therapy is one of the most common treatments for non-small cell lung cancer (NSCLC). However, the insensitivity of some tumor cells to radiation is one of the major reasons for the poor efficacy of radiotherapy and the poor prognosis of patients, and exploring the underlying mechanisms behind radioresistance is the key to solving this clinical challenge. This study aimed to identify the molecules associated with radioresistance in lung adenocarcinoma (LUAD), identified thyroid hormone receptor interactor 13 (TRIP13) as the main target initially, and explored whether TRIP13 is related to radioresistance in LUAD and the specific mechanism, with the aim of providing theoretical basis and potential targets for the combination therapy of LUAD patients receiving radiotherapy in the clinic.@*METHODS@#Three datasets, GSE18842, GSE19188 and GSE33532, were selected from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (|log FC|>1.5, P<0.05) in each of the three datasets using the R 4.1.3 software, and then Venn diagram was used to find out the differentially expressed genes common to the three datasets. The screened differential genes were then subjected to protein-protein interaction (PPI) analysis and module analysis with the help of STRING online tool and Cytoscape software, and survival prognosis analysis was performed for each gene with the help of Kaplan-Meier Plotter database, and the TRIP13 gene was identified as the main molecule for subsequent studies. Subsequently, the human LUAD cell line H292 was irradiated with multiple X-rays using a sub-lethal dose irradiation method to construct a radioresistant cell line, H292DR. The radioresistance of H292DR cells was verified using cell counting kit-8 (CCK-8) assay and clone formation assay. The expression levels of TRIP13 in H292 and H292DR cells were measured by Western blot. Small interfering RNA (siRNA) was used to silence the expression of TRIP13 in H292DR cells and Western blot assay was performed. The clone formation ability and migration ability of H292DR cells were observed after TRIP13 silencing, followed by the detection of changes in the expression levels of proteins closely related to homologous recombination, such as ataxia telangiectasia mutated (ATM) protein.@*RESULTS@#Screening of multiple GEO datasets, validation of external datasets and survival analysis revealed that TRIP13 was highly expressed in LUAD and was associated with poor prognosis in LUAD patients who had received radiation therapy. And the results of gene set enrichment analysis (GSEA) of TRIP13 suggested that TRIP13 might be closely associated with LUAD radioresistance by promoting homologous recombination repair after radiation therapy. Experimentally, TRIP13 expression was found to be upregulated in H292DR, and silencing of TRIP13 was able to increase the sensitivity of H292DR cells to radiation.@*CONCLUSIONS@#TRIP13 is associated with poor prognosis in LUAD patients treated with radiation, possibly by promoting a homologous recombination repair pathway to mediate resistance of LUAD cells to radiation.

A Case of New Rapidly Progressing Ground-glass Nodule Lung Adenocarcinoma Near Primary Lesion after Stereotactic Body Radiation Therapy / 中国肺癌杂志

Ground-glass nodule (GGN) lung cancer often progresses slowly in clinical and there are few clinical studies on long-term follow-up of patients with operable GGN lung cancer treated with stereotactic body radiation therapy (SBRT). We present a successful case of GGN lung cancer treated with SBRT, but a new GGN was found in the lung adjacent to the SBRT target during follow-up. The nodule progressed rapidly and was confirmed as lung adenocarcinoma by surgical resection. No significant risk factors and related driving genes were found in molecular pathological findings and genetic tests. It deserves further study whether new GGN is related to the SBRT. This case suggests that the follow-up after SBRT should be vigilant against the occurrence of new rapidly progressive lung cancer in the target area and adjacent lung tissue.
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Mutational Signatures Analysis of Micropapillary Components and Exploration of ZNF469 Gene in Early-stage Lung Adenocarcinoma with Ground-glass Opacities / 中国肺癌杂志

BACKGROUND@#In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration.@*METHODS@#A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases.@*RESULTS@#MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05).@*CONCLUSIONS@#The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.

TTYH3 is a prognostic biomarker and associates with immune cell infiltrations of lung adenocarcinoma / TTYH3 es un biomarcador pronóstico y se asocia con infiltraciones de células inmunitarias del adenocarcinoma de pulmón

SUMMARY: We investigated Tweety Family Member 3 (TTYH3) level in lung adenocarcinoma (LUAD) and its relationship with immune infiltration in tumors by bioinformatics. Differential expressions of TTYH3 in lung cancer were analyzed with Oncomine, TIMER, GEO, UALCAN and HPA. Relationship of TTYH3 mRNA/protein levels with clinical parameters was analyzed by UALCAN. Co-expressed genes of TTYH3 in LUAD were analyzed using Cbioportal. Its relationship with LUAD prognosis was analyzed by Kaplan-Meier plotter. GO and KEGG analysis were performed. Correlation between TTYH3 and tumor immune infiltration were tested by TIMER, TISIDB and GEPIA. We found that TTYH3 was significantly increased in LUAD tissues. TTYH3 high expression was closely related to poor overall survival, post progression survival and first progression in LUAD patients. TTYH3 mRNA/protein levels were significantly associated with multiple pathways. Specifically, TTYH3 up-regulation was mostly related to biological regulation, metabolic process, protein blinding, extracellular matrix organization and pathways in cancer. Moreover, TTYH3 was positively associated with immune cell infiltration in LUAD. Finally, TTYH3 was highly expressed in LUAD as revealed by meta-analysis. TTYH3 is closely related to the prognosis of LUAD and immune cell infiltration, and it can be used as a prognostic biomarker for LUAD and immune infiltration.

Investigamos por bioinformática el nivel de Tweety Family Member 3 (TTYH3) con adenocarcinoma de pulmón (LUAD) y su relación con la infiltración inmune en tumores. Las expresiones diferenciales de TTYH3 en cáncer de pulmón se analizaron con Oncomine, TIMER, GEO, UALCAN y HPA. Con UALCAN se analizó la relación de los niveles de ARNm/proteína de TTYH3 con los parámetros clínicos. Los genes coexpresados de TTYH3 en LUAD se analizaron utilizando Cbioportal. Su relación con el pronóstico LUAD se analizó mediante plotter de Kaplan- Meier. Se realizaron análisis GO y KEGG. TIMER, TISIDB y GEPIA probaron la correlación entre TTYH3 y la infiltración inmune tumoral. Encontramos que TTYH3 aumentó significativamente en los tejidos LUAD. La alta expresión de TTYH3 estuvo estrechamente relacionada con una supervivencia general deficiente, supervivencia posterior a la progresión y primera progresión en pacientes con LUAD. Los niveles de ARNm/ proteína de TTYH3 se asociaron significativamente con múltiples vías. Específicamente, la regulación positiva de TTYH3 se relacionó principalmente con la regulación biológica, el proceso metabólico, el cegamiento de proteínas, la organización de la matriz extracelular y las vías en el cáncer. Además, TTYH3 se asoció positivamente con la infiltración de células inmunitarias en LUAD. Finalmente, TTYH3 se expresó altamente en LUAD como lo reveló el metanálisis. TTYH3 está estrechamente relacionado con el pronóstico de LUAD y la infiltración de células inmunitarias, y se puede utilizar como biomarcador pronóstico para LUAD y la infiltración de células inmunitarias.

S100A10 promotes proliferation and invasion of lung adenocarcinoma cells by activating the Akt-mTOR signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effects of expression levels of S100 calcium-binding protein A10 (S100A10) in lung adenocarcinoma (LUAD) on patient prognosis and the regulatory role of S100A10 in lung cancer cell proliferation and metastasis.@*METHODS@#Immunohistochemistry was used to detect the expression levels of S100A10 in LUAD and adjacent tissues, and the relationship between S100A10 expression and clinicopathological parameters and prognosis of the patients was statistically analyzed. The lung adenocarcinoma expression dataset in TCGA database was analyzed using gene enrichment analysis (GSEA) to predict the possible regulatory pathways of S100A10 in the development of lung adenocarcinoma. Lactate production and glucose consumption of lung cancer cells with S100A10 knockdown or overexpression were analyzed to assess the level of glycolysis. Western blotting, CCK-8 assay, EdU-594 assay, and Transwell assays were performed to determine the expression level of S100A10 protein, proliferation and invasion ability of lung cancer cells. A549 cells with S100A10 knockdown and H1299 cells with S100A10 overexpression were injected subcutaneously in nude mice, and tumor growth was observed.@*RESULTS@#The expression level of S100A10 was significantly upregulated in LUAD tissues as compared with the adjacent tissues, and an elevated S100A10 expression level was associated with lymph node metastasis, advanced tumor stage and distant organ metastasis (P < 0.05), but not with tumor differentiation or the patients' age or gender (P > 0.05). Survival analysis showed that elevated S100A10 expressions in the tumor tissue was associated with a poor outcome of the patients (P < 0.001). In the lung cancer cells, S100A10 overexpression significantly promoted cell proliferation and invasion in vitro (P < 0.001). GSEA showed that the gene sets of glucose metabolism, glycolysis and mTOR signaling pathway were significantly enriched in high expressions of S100A10. In the tumor-bearing nude mice, S100A10 overexpression significantly promoted tumor growth, while S100A10 knockdown obviously suppressed tumor cell proliferation (P < 0.001).@*CONCLUSION@#S100A10 overexpression promotes glycolysis by activating the Akt-mTOR signaling pathway to promote proliferation and invasion of lung adenocarcinoma cells.

Perianal Paget 's disease complicated with lung adenocarcinoma and anal canal carcinoma: A case report and literature review / 中南大学学报(医学版)

Perianal Paget's disease (PPD) is a rare malignant cutaneous tumor. This paper reported a case of PPD complicated by lung adenocarcinoma and anal canal cancer. The patient, a 76-year-old female, had been experiencing recurrent lower abdominal pain and perianal pruritus for the past 5 years. Upon physical examination, a cauliflower-like neoplasm in size of 5 cm×6 cm was observed on the right perianal skin, with local skin ulceration and a small amount of fluid discharge. The left perianal skin was also involved. In thoracoknee position, a hard mass was palpable in the rectal submucosa at 5-6 points 2 cm from the anal verge. Chest CT revealed multiple lesions in both lungs, indication of metastatic tumors. Further evaluation with fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) indicated multiple hypermetabolic nodules in the lungs, hypermetabolic lymph nodes throughout the body, early FDG uptake in a small patch of skin on the left hip, and increased FDG uptake in the anorectal region. Histopathological examination confirmed the diagnosis of lung adenocarcinoma. This resulted in the patient being diagnosed with PPD, lung adenocarcinoma, anal canal cancer, and systemic multiple lymph node metastasis. The combination of PPD with gastrointestinal tumors and other metachronous malignant tumors is highly prevalent. Colonoscopy, FDG-PET/CT, histopathology, and immunohistochemistry play crucial roles in early identification of local lymph node and distant involvement, facilitating the evaluation of potential malignant tumors and differential diagnosis. Treating methods for PPD are currently diverse, including postoperative combined or single chemotherapy, radiotherapy, targeted therapy, and photodynamic therapy. As trerapeutical options continue to develop, the extent and efficacy of surgery need to be reassessed.

Mechanism of miR-186-5p Regulating PRKAA2 to Promote Ferroptosis in Lung Adenocarcinoma Cells / 中国肺癌杂志

BACKGROUND@#Lung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer, and any change of miRNAs expression will affect the degree of target regulation, thus affecting intracellular homeostasis. This study verified that miR-186-5p could inhibit the proliferation, migration and invasion of LUAD cells by regulating PRKAA2.@*METHODS@#Previous investigations found that the expression of miR-186-5p was markedly suppressed in LUAD. Bioinformatics method is used to predict the target protein related to ferroptosis downstream and inquire about its expression level in LUAD and its influence on the survival of patients. Double luciferase verified the binding site of PRKAA2 and miR-186-5p. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of PRKAA2. The effects of miR-186-5p of LUAD cells as well as the mechanism by which miR-186-5p inhibits Fer-1's sensitivity to ferroptosis were confirmed by EdU, Transwell, and scratch assays. The effect of miR-186-5p on the amount of reactive oxygen species (ROS) in LUAD cells was discovered using ROS experiment. Malondialdehyde (MDA) and glutathione (GSH) experiments were used to detect the effects of miR-186-5p and PRKAA2 on ferroptosis index of LUAD cells. The concentration of lipid ROS (L-ROS) in LUAD cells were measured using the L-ROS tests to determine the effects of miR-186-5p and PRKAA2.@*RESULTS@#The expression of PRKAA2 is up-regulated, and a high level of PRKAA2 expression was associated with a poor prognosis for patients with LUAD. Overexpression of miR-186-5p decreased the gene and protein expression of PRKAA2. By promoting ferroptosis, miR-186-5p overexpression prevented lung cancer cells from proliferating, invading, and migrating. ROS could be produced in higher amounts in LUAD cells due to miR-186-5p. Overexpression of miR-186-5p and knockdown PRKAA2 up-regulated MDA content and reduced GSH content in LUAD cells, respectively. miR-186-5p could increase the content of L-ROS and promote the ferroptosis sensitivity of LUAD cells by targeting PRKAA2.@*CONCLUSIONS@#miR-186-5p promotes ferroptosis of LUAD cells through targeted regulation of PRKAA2, thus inhibiting the proliferation, invasion and migration of LUAD.
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A Rare Case of Lung Adenocarcinoma with EGFR L833V/H835L Co-mutation and Literature Review / 中国肺癌杂志

Epidermal growth factor receptor (EGFR) mutations are the most common driver genes in the development of non-small cell lung cancer (NSCLC), of which mutations in exons 18-21 are frequent, especially the loss of exon 19 and exon 21 L858R mutation are the most frequent. Other rare gene mutations are rare. Simultaneous occurrence of two or more rare EGFR mutations are extremely rare in lung cancer, and the incidence of EGFR L833V/H835L rare gene compound mutations is very low, and there is little clinical data and evidence of relevant treatment methods. Some EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are effective in treating lung cancer patients with rare gene mutations. In this article, we reported a case of NSCLC patient with a rare gene compound mutation EGFR L833V/H835L, who responded to Afatinib in combination with Anilotinib treatment well after 5 months of treatment, and computed tomography (CT) showed shrinkage of lung lesions. Meanwhile, we also compiled previously reported NSCLC patients with EGFR L833V/H835L rare gene compound mutation and summarized the characteristics of this group of patients and the effect of applying different kinds of EGFR-TKIs treatment.
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miR-218-5p Targeting TPX2 Regulates p53 Pathway and Inhibits Malignant Progression of Lung Adenocarcinoma / 中国肺癌杂志

BACKGROUND@#Lung adenocarcinoma (LUAD) is a major subtype of lung cancer, and its treatment and diagnosis remain a hot research topic. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is highly expressed in a variety of cancer cells and may be associated with the progression of LUAD. This study aimed to investigate the effect of TPX2 on the malignant progression of LUAD cells and the regulatory mechanisms.@*METHODS@#The expression of gene TPX2 in LUAD tissues from The Cancer Genome Atlas (TCGA) database was analyzed by bioinformatics analysis techniques. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of TPX2 and miR-218-5p in human lung normal cell lines and human LUAD cell lines. Western blot was used to detect TPX2 protein expression in cell lines and its effect on the expression of key proteins in the p53 signaling pathway. The relationship between TPX2 and miR-218-5p was predicted using bioinformatics and verified by dual luciferase reporter gene assay. Cell counting kit-8 (CCK-8) assay, cell clone formation, cell scratching, Transwell assay, and flow cytometry were used to detect the effects of miR-218-5p and TPX2 on LUAD cell function.@*RESULTS@#TPX2 was significantly overexpressed in LUAD cells, and knockdown of TPX2 inhibited LUAD cell proliferation, migration, and invasion, promoted apoptosis and induced G2/M phase block, and promoted the expression of key proteins in the p53 signaling pathway. miR-218-5p, an upstream regulator of TPX2, could inhibit its expression. Overexpression of miR-218-5p eliminated the malignant development caused by high expression of TPX2, inhibited the malignant processes of LUAD cells such as proliferation and migration as well as promoted the p53 signaling pathway.@*CONCLUSIONS@#miR-218-5p targets and inhibits TPX2 expression and exerts an inhibitory effect on the malignant progression of LUAD cells via p53.

Immune Checkpoint Inhibitors Related Cystoureteritis: A Case Report and Literature Review / 中国肺癌杂志

A patient with advanced lung adenocarcinoma developed symptoms of frequent urination and urgent urination after 14 cycles of Pembrolizumab combined with chemotherapy. After making comprehensive analysis of the results of urine routine test, renal function, cystoscope and computed tomography (CT) examination, immune checkpoint inhibitors related cystoureteritis and acute kidney injury were considered. The patient's symptoms were relieved after discontinuation of Pembrolizumab combined with chemotherapy. However, the symptoms of urinary irritation worsened significantly after rechallenging Pembrolizumab combined with chemotherapy, and the symptoms was relieved after corticosteroids treatment. If patients develop urinary symptoms during immune checkpoint inhibitors treatment, immune checkpoint inhibitors related cystoureteritis should be considered for early differential diagnosis in order to implement appropriate treatment.
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Identification of SULF1 as a Shared Gene in Idiopathic Pulmonary Fibrosis and Lung Adenocarcinoma / 中国肺癌杂志

BACKGROUND@#Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer.@*METHODS@#Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases.@*RESULTS@#A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts.@*CONCLUSIONS@#This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.

Analysis of Clinicopathological Features on Spread Through Air Spaces of Lung Adenocarcinoma / 中国肺癌杂志

BACKGROUND@#The biological and molecular characteristics of spread through air spaces (STAS), a newly recognized invasive mode of lung cancer, remain controversial. The aim of this study was to investigate the clinicopathological features and molecular characteristics of STAS in patients with pulmonary adenocarcinoma.@*METHODS@#A total of 694 resected invasive non-mucinous lung adenocarcinomas diagnosed by clinicopathology from July 2019 to March 2021 in the First Affiliated Hospital of Guangzhou Medical University were collected, and the relationship between STAS and clinicopathological factors was analyzed. The state of protein expression of anaplastic lymphoma kinase (ALK) was detected by immunohistochemical method. Epidermal growth factor receptor (EGFR) was detected by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). ROS proto-oncogene 1-receptor (ROS1) was detected by reverse transcription-PCR (RT-PCR).@*RESULTS@#A total of 344 STAS positive cases and 350 STAS negative cases were collected. By univariate analysis, STAS positivity was statistically associated with tumor maximum diameter (P<0.001), pleural invasion (P<0.001), lymphovascular invasion (P<0.001), nerve invasion (P=0.013), lymph node metastasis (P<0.001), clinical stage (P<0.001) and histological type (P<0.001). There was a statistical correlation between STAS and ALK protein expression (P=0.001). Multivariate analysis showed that STAS positive was correlated with pleural invasion (P=0.001), vascular invasion (P<0.001), lymph node metastasis (P=0.005)and ALK protein expression (P=0.032).@*CONCLUSIONS@#STAS is associated with highly aggressive biological behavior of lung adenocarcinoma, suggesting a poor prognosis.

Construction of Lung Adenocarcinoma Prognosis Model and Drug Sensitivity Analysis Based on Cuproptosis Related Genes / 中国肺癌杂志

BACKGROUND@#Lung cancer is one of the most common malignant tumors in the world, and the current lung cancer screening and treatment strategies are constantly improving, but its 5-year survival rate is still very low, which seriously endangers human health. Therefore, it is critical to explore new biomarkers to provide personalized treatment and improve the prognosis. Cuproptosis is a newly discovered type of cell death, which is due to the accumulation of excess copper ions in the cell, eventually leading to cell death, which has been suggested by studies to be closely related to the occurrence and development of lung adenocarcinoma (LUAD). Based on The Cancer Genome Atlas (TCGA) database, this study explored the association between cuproptosis-related genes (CRGs) and LUAD prognosis, established a prognostic risk model, and analyzed the interaction between CRGs and LUAD immune cell infiltration.@*METHODS@#The RNA-seq data of LUAD tissue and paracancerous or normal lung tissue were downloaded from the TCGA database; the RNA-seq data of normal lung tissue was downloaded from the Genotype-tissue Expression (GTEx) database, and the data of 462 lung adenocarcinoma cases were downloaded from the Gene Expression Omnibus repository (GEO) as verification. T the risk score model to assess prognosis was constructed by univariate Cox and Lasso-Cox regression analysis, and the predictive ability of the model was evaluated by receiver operating characteristic (ROC) curve and calibration curve. Immune-related and drug susceptibility analysis was further performed on high- and low-risk groups.@*RESULTS@#A total of 1656 CRGs and 1356 differentially expressed CRGs were obtained, and 13 CRGs were screened out based on univariate Cox and Lasso-Cox regression analysis to construct a prognostic risk model, and the area under the curves (AUCs) of ROC curves 1-, 3- and 5- year were 0.749, 0.740 and 0.689, respectively. Further study of immune-related functions and immune checkpoint differential analysis between high- and low-risk groups was done. High-risk groups were more sensitive to drugs such as Savolitinib, Palbociclib, and Cytarabine and were more likely to benefit from immunotherapy.@*CONCLUSIONS@#The risk model constructed based on 13 CRGs has good prognostic value, which can assist LUAD patients in individualized treatment, and provides an important theoretical basis for the treatment and prognosis of LUAD.

Role of Eukaryotic Translation Elongation Factor 1 Family Members in the Tumorigenesis and Progression of Lung Adenocarcinoma / 中国医学科学院学报

Objective To investigate the role and mechanism of eukaryotic translation elongation factor 1(EEF1) family members (EEF1D,EEF1A1,and EEF1A2) in lung adenocarcinoma (LUAD) based on public databases.Methods We examined EEF1 member expression levels in human LUAD samples via The Cancer Genome Atlas in the UCSC Xena browser and the Clinical Proteomic Tumor Analysis Consortium.We analyzed the mRNA and protein levels of EEF1D,EEF1A1,and EEF1A2 and their correlations with pathological variables via the Mann-Whitney U test.The Kaplan-Meier curves were established to assess the prognostic values of EEF1D,EEF1A1,and EEF1A2.The single-sample gene set enrichment analysis algorithm was employed to explore the relationship between the expression levels of EEF1 members and tumor immune cell infiltration.Spearman and Pearson correlation analyses were performed to examine the relationship between the expression levels of EEF1 members and those of the genes in the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.The immunohistochemical assay was employed to determine the expression levels of EEF1D,EEF1A1,and EEF1A2 in the LUAD tissue (n=75) and paracancer tissue (n=75) samples.Results The mRNA and protein levels of EEF1D,EEF1A1,and EEF1A2 showed significant differences between tumor and paracancer tissues (all P<0.001).The patients with high protein levels of EEF1A1 showed bad prognosis in terms of overall survival (P=0.039),and those with high protein levels of EEF1A2 showed good prognosis in terms of overall survival (P=0.012).The influence of the mRNA level of EEF1D on prognosis was associated with pathological characteristics.The expression levels of EEF1 members were significantly associated with the infiltration of various immune cells and the expression of key molecules in the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.Conclusion EEF1D,EEF1A1,and EEF1A2 are associated with the progression of LUAD,serving as the candidate prognostic markers for LUAD.

Clinicopathological Features and Prognosis of Patients Newly Diagnosed With Lung Adenocarcinoma With Both EGFR Mutation and C-MET Amplification / 中国医学科学院学报

Objective To explore the clinicopathological features and prognosis of the patients newly diagnosed with lung adenocarcinoma with both EGFR mutation and C-MET amplification.Methods The pathological sections were reviewed.EGFR mutation was detected by amplification refractory mutation system-quantitative real-time polymerase chain reaction,and C-MET amplification by fluorescence in situ hybridization.The clinicopathological features and survival data of the patients newly diagnosed with lung adenocarcinoma with both EGFR mutation and C-MET amplification were analyzed retrospectively.Results In 11 cases of EGFR mutation combined with C-MET amplification,complex glands and solid high-grade components were observed under a microscope in 10 cases except for one case with a cell block,the tissue structure of which was difficult to be evaluated.The incidence of lung adenocarcinoma in the patients with EGFR mutation combined with C-MET amplification at clinical stage Ⅳ was higher than that in the EGFR mutation or C-MET amplification group (all P<0.001),whereas the difference was not statistically significant between the EGFR mutation group and C-MET amplification group at each clinical stage (all P>0.05).There was no significant difference in the trend of survival rate between EGFR gene group and C-MET amplification group (χ2=0.042,P=0.838),while the survival of the patients with EGFR mutation combined with C-MET amplification was worse than that of the patients with EGFR mutation (χ2=246.72,P<0.001) or C-MET amplification (χ2=236.41,P<0.001).Conclusions The patients newly diagnosed with lung adenocarcinoma with EGFR mutation plus C-MET amplification demonstrate poor histological differentiation,rapid progress,and poor prognosis.The patients are often in the advanced stage when being diagnosed with cancer.Attention should be paid to this concurrent adverse driving molecular event in clinical work.With increasing availability,the inhibitors targeting C-MET may serve as an option to benefit these patients in the near future.

Role of Prognostic Marker PRR11 in Immune Infiltration for Facilitating Lung Adenocarcinoma Progression / 生物医学与环境科学（英文）

The PRR11 gene (Proline Rich 11) has been implicated in lung cancer; however, relationship between PRR11 and immune infiltration is not clearly understood. In this study, we used The Cancer Genome Atlas (TCGA) data to analyze the lung adenocarcinoma patients; PRR11 gene expression, clinicopathological findings, enrichment, and immune infiltration were also studied. PRR11 immune response expression assays in lung adenocarcinoma (LUAD) were performed using TIMER, and statistical analysis and visualization were conducted using R software. All data were verified using Gene Expression Profiling Interactive Analysis (GEPIA), and the Human Protein Atlas (HPA). We found that PRR11 was an important prognostic factor in patients with LUAD. PRR11 expression was correlated with tumor stage and progression. Gene Set Enrichment Analysis (GSEA) showed that PRR11 was enriched in the cell cycle regulatory pathways. Immune infiltration analysis revealed that the number of T helper 2 (Th2) cells increased when PRR11 was overexpressed. These results confirm the role of PRR11 as a prognostic marker of lung adenocarcinoma by controlling the cell cycle and influencing the immune system to facilitate lung cancer progression.

Diagnostic yield of bronchoscopic rapid on-site evaluation in severe invasive bronchopulmonary aspergillosis / 中华危重病急救医学

OBJECTIVE@#To explore the diagnostic yield of bronchoscopic rapid on-site evaluation (B-ROSE) in patients with severe invasive bronchopulmonary aspergillosis (IBPA) and provide evidence for starting antifungal treatment before microbiological results were available.@*METHODS@#A prospective cohort study was conducted to select patients with severe pneumonia suspected of IBPA admitted to the respiratory intensive care unit (RICU) in the First Affiliated Hospital of Xinjiang Medical University from June 2014 to June 2022, and those who were primarily infected with other pathogens (such as bacteria, Mycobacterium tuberculosis) at admission were excluded. Whether the antifungal treatment was initiated or not on the basis of the bedside B-ROSE, the B-ROSE was administered as soon as possible within 24 hours after admission to RICU. The current international definition of invasive aspergillosis was used as the gold diagnostic standard, the diagnostic accordance rate, the sensitivity and specificity of B-ROSE were calculated respectively, and the receiver operator characteristic curve (ROC curve) was also plotted, to evaluate the predictive value in diagnosing IBPA.@*RESULTS@#A total of 176 patients with severe pneumonia suspected of IBPA were included in the study. According to international diagnostic standards, there were 81 cases of IBPA and 95 cases of non-IBPA. According to the early diagnosis of B-ROSE, there were 89 cases of IBPA and 87 cases of non-IBPA. The diagnostic accordance rate of B-ROSE was 84.09% (148/176), the area under the ROC curve for B-ROSE in diagnosing severe IBPA was 0.844, the 95% confidence interval (95%CI) was 0.782-0.905, the sensitivity was 87.65%, the specificity was 81.05%, the positive predictive value was 79.78%, the negative predictive value was 88.51%, the rate of underdiagnosis was 12.35% (10/81), and the rate of misdiagnosis was 18.95% (18/95). Compared with the true negative group, the proportion of long-term (≥ 14 days) use of glucocorticoid [70.0% (7/10) vs. 9.1% (7/77), P < 0.01] and the proportion of cases with diabetes [40.0% (4/10) vs. 10.4% (8/77), P < 0.05] were significantly higher in the false negative group (underdiagnosis group). However, B-ROSE of both groups showed mucosal bleeding, congestion and edema [100.0% (10/10) vs. 94.8% (73/77), P > 0.05], indicating that acute mucosal inflammation was non-characteristic. Compared with the true positive group, the proportion of long-term (≥ 14 days) use of glucocorticoid in the false positive group (misdiagnosis group) was significantly reduced [33.3% (6/18) vs. 60.6% (43/71), P < 0.05]. The B-ROSE results showed the proportion of cases with mucosal white spots, black plaques and pseudomembrane was significantly reduced [16.7% (3/18) vs. 52.1% (37/71), P < 0.01] in the misdiagnosed group, which suggest that cases of long-term use of glucocorticoid and cases with B-ROSE showing mucosal white spots, black plaques and pseudomembrane were less likely to be misdiagnosed. The main diseases that were easily misdiagnosed as IBPA included pulmonary tuberculosis (38.9%, 7/18), inflammatory lung adenocarcinoma (27.8%, 5/18) and pulmonary vasculitis (16.7%, 3/18).@*CONCLUSIONS@#Before obtaining microbiological evidence, B-ROSE can assist in decision-making of early anti-aspergillus treatment for severe IBPA. This method is prompt, simple, and has high accuracy and reliability. If B-ROSE lacks characteristic manifestations, especially for severe pneumonia in patients with long-term use of glucocorticoid or diabetes, attention should be paid to the underdiagnosis of IBPA. Diseases such as lung tuberculosis, inflammatory lung adenocarcinoma and lung vasculitis should be vigilant against misdiagnosis as IBPA.

Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation / 中国结合医学杂志

OBJECTIVE@#To investigate the mechanism of the effect of Astragalus membranaceus (A. membranaceus) on lung adenocarcinoma at the molecular level to elucidate the specific targets according to the network pharmacology approach.@*METHODS@#The active components of A. membranaceus and their potential targets were collected from the Traditional Chinese Medicine Systems Pharmacology Database. Lung adenocarcinoma-associated genes were acquired based on GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGKB, and Therapeutic Targets databases. The PI3K/AKT signaling pathway-related genes were obtained using Reactome portal. Networks of "ingredient-target" and "ingredient-target-pathway-disease" were constructed using the Cytoscape3.6.0 software. The relationships among targets were analyzed according protein-protein interaction (PPI) network. Finally, molecular docking was applied to construct the binding conformation between active ingredients and core targets. Cell counting kit 8 (CCK8) and Western blot assays were performed to determine the mechanism of the key ingredient of A. membranaceus.@*RESULTS@#A total of 20 active components and their 329 targets, and 7,501 lung adenocarcinoma-related genes and 130 PI3K/AKT signaling pathway-related genes were obtained. According to Venn diagram and PPI network analysis, 2 mainly active ingredients, including kaempferol and quercetin, and 6 core targets, including TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR, were identified. The two important active ingredients of A. membranaceus, kaempferol and quercetin, exert the therapeutic effect in lung adenocarcinoma partly by acting on the 6 core targets (TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR) of PI3K/AKT signaling pathway. Expressions of potential targets in lung adenocarcinoma and normal samples were analyzed by using UALCAN portal and found that ERBB2 was overexpressed in lung adenocarcinoma tissues and upregulation of it correlated with clinicopathological characteristics. Finally, quercetin repressed viabilities of lung adenocarcinoma cells by targeting ERBB2 on PI3K/AKT signaling confirmed by CCK8 and Western blot.@*CONCLUSION@#Our finding unraveled that an active ingredient of A. membranaceus, quercetin, significantly inhibited the lung adenocarcinoma cells proliferation by repressing ERBB2 level and inactivating the PI3K/AKT signaling pathway.