What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years.

BACKGROUND: Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on LCBM, problems have emerged, such as confusing research structures. AIM: To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation, clinical treatment, and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research. METHODS: We used tools, including R, VOSviewer and CiteSpace software, to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection. We also performed enrichment and protein-protein interaction analyses of gene expression datasets from LCBM cases worldwide. RESULTS: Research on LCBM has received extensive attention from scholars worldwide over the last 20 years. Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions. The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis. The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence. CONCLUSION: Novel therapies for LCBM face animal testing and drug resistance issues. Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.

Hsa_circ_0096157 silencing suppresses autophagy and reduces cisplatin resistance in non-small cell lung cancer by weakening the Nrf2/ARE signaling pathway.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer morbidity and mortality worldwide, and new diagnostic markers are urgently needed. We aimed to investigate the mechanism by which hsa_circ_0096157 regulates autophagy and cisplatin (DDP) resistance in NSCLC. METHODS: A549 cells were treated with DDP (0 µg/mL or 3 µg/mL). Then, the autophagy activator rapamycin (200 nm) was applied to the A549/DDP cells. Moreover, hsa_circ_0096157 and Nrf2 were knocked down, and Nrf2 was overexpressed in A549/DDP cells. The expression of Hsa_circ_0096157, the Nrf2/ARE pathway-related factors Nrf2, HO-1, and NQO1, and the autophagy-related factors LC3, Beclin-1, and p62 was evaluated by qRT‒PCR or western blotting. Autophagosomes were detected through TEM. An MTS assay was utilized to measure cell proliferation. The associated miRNA levels were also tested by qRT‒PCR. RESULTS: DDP (3 µg/mL) promoted hsa_circ_0096157, LC3 II/I, and Beclin-1 expression and decreased p62 expression. Knocking down hsa_circ_0096157 resulted in the downregulation of LC3 II/I and Beclin-1 expression, upregulation of p62 expression, and decreased proliferation. Rapamycin reversed the effect of interfering with hsa_circ_0096157. Keap1 expression was lower, and Nrf2, HO-1, and NQO1 expression was greater in the A549/DDP group than in the A549 group. HO-1 expression was repressed after Nrf2 interference. In addition, activation of the Nrf2/ARE pathway promoted autophagy in A549/DDP cells. Moreover, hsa_circ_0096157 activated the Nrf2/ARE pathway. The silencing of hsa_circ_0096157 reduced Nrf2 expression by releasing miR-142-5p or miR-548n. Finally, we found that hsa_circ_0096157 promoted A549/DDP cell autophagy by activating the Nrf2/ARE pathway. CONCLUSION: Knockdown of hsa_circ_0096157 inhibits autophagy and DDP resistance in NSCLC cells by downregulating the Nrf2/ARE signaling pathway.

Clinical significance and potential pathogenesis of VCAN in adult non-cystic fibrosis bronchiectasis: a retrospective study.

BACKGROUND: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis. METHODS: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay. RESULTS: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001). CONCLUSIONS: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis.

A novel prognostic signature of coagulation-related genes leveraged by machine learning algorithms for lung squamous cell carcinoma.

Coagulation-related genes (CRGs) have been demonstrated to be essential for the development of certain tumors; however, little is known about CRGs in lung squamous cell carcinoma (LUSC). In this study, we adopted CRGs to construct a coagulation-related gene prognostic signature (CRGPS) using machine learning algorithms. Using a set of 92 machine learning integrated algorithms, the CRGPS was determined to be the optimal prognostic signature (median C-index = 0.600) for predicting the prognosis of an LUSC patient. The CRGPS was not only superior to traditional clinical parameters (e.g., T stage, age, and gender) and its commutative genes but also outperformed 19 preexisting prognostic signatures for LUSC on predictive accuracy. The CRGPS score was positively correlated with poor prognoses in patients with LUSC (hazard ratio > 1, p < 0.05), indicating its suitability as a prognostic marker for this disease. The CRGPS was observed to be inversely correlated with the degree of infiltration of natural killer cells. For some tumors, patients with lower CRGPS scores are more likely to experience enhanced immunotherapy effects (area under the curve = 0.70), which implies that the CRGPS can potentially predict immunotherapy efficacy. A high CRGPS score is predictive of an LUSC patient being sensitive to several drugs. Collectively, these findings indicate that the CRGPS may be a reliable indicator of the prognoses of patients with LUSC and may be useful for the clinical management of such patients.

MMP12 is a Potential Predictive and Prognostic Biomarker of Various Cancers Including Lung Adenocarcinoma.

OBJECTIVE: This study sought to explore the clinical value of matrix metalloproteinases 12 (MMP12) in multiple cancers, including lung adenocarcinoma (LUAD). METHODS: Using >10,000 samples, this retrospective study demonstrated the first pan-cancer analysis of MMP12. The expression of MMP12 between cancer groups and their control groups was analyzed using Wilcoxon rank-sum tests. The clinical significance of MMP12 expression in multiple cancers was assessed using receiver operating characteristic curves, Kaplan-Meier curves, and univariate Cox analysis. A further LUAD-related analysis based on 4565 multi-center and in-house samples was performed to verify the findings regarding MMP12 in pan-cancer analysis partly. RESULTS: MMP12 mRNA is highly expressed in 13 cancers compared to their controls, and the MMP12 protein level is elevated in some of these cancers (e.g., colon adenocarcinoma) (P < .05). MMP12 expression makes it feasible to distinguish 21 cancer tissues from normal tissues (AUC = 0.86). A high MMP12 expression is a prognosis risk factor in eight cancers, such as adrenocortical carcinoma (hazard ratio >1, P < .05). The elevated MMP12 expression is also a prognosis protective factor in breast-invasive carcinoma and colon adenocarcinoma (hazard ratio <1, P < .05). Some pan-cancer findings regarding MMP12 are verified in LUAD-MMP12 expression is upregulated in LUAD at both the mRNA and protein levels (P < .05), has the potential to distinguish LUAD with considerable accuracy (AUC = .91), and plays a risk prognosis factor for patients with the disease (P < .05). CONCLUSIONS: MMP12 is highly expressed in most cancers and may serve as a novel biomarker for the prediction and prognosis of numerous cancers.

MMP12 serves as an immune cell-related marker of disease status and prognosis in lung squamous cell carcinoma.

Background: Worldwide, lung squamous cell carcinoma (LUSC) has wreaked havoc on humanity. Matrix metallopeptidase 12 (MMP12) plays an essential role in a variety of cancers. This study aimed to reveal the expression, clinical significance, and potential molecular mechanisms of MMP12 in LUSC. Methods: There were 2,738 messenger RNA (mRNA) samples from several multicenter databases used to detect MMP12 expression in LUSC, and 125 tissue samples were validated by immunohistochemistry (IHC) experiments. Receiver operator characteristic (ROC) curves, Kaplan-Meier curves, and univariate and multivariate Cox regression analyses were used to assess the clinical value of MMP12 in LUSC. The potential molecular mechanisms of MMP12 were explored by gene enrichment analysis and immune correlation analysis. Furthermore, single-cell sequencing was used to determine the distribution of MMP12 in multiple tumor microenvironment cells. Results: MMP12 was significantly overexpressed at the mRNA level (p < 0.05, SMD = 3.13, 95% CI [2.51-3.75]), which was verified at the protein level (p < 0.001) by internal IHC experiments. MMP12 expression could be used to differentiate LUSC samples from normal samples, and overexpression of MMP12 itself implied a worse clinical prognosis and higher levels of immune cell infiltration in LUSC patients. MMP12 was involved in cancer development and progression through two immune-related signaling pathways. The high expression of MMP12 in LUSC might act as an antigen-presenting cell-associated tumor neoantigen and activate the body's immune response. Conclusions: MMP12 expression is upregulated in LUSC and high expression of MMP12 serves as a risk factor for LUSC patients. MMP12 may be involved in cancer development by participating in immune-related signaling pathways and elevating the level of immune cell infiltration.

CEP55: an immune-related predictive and prognostic molecular biomarker for multiple cancers.

BACKGROUND: Centrosomal protein 55 (CEP55) plays a significant role in specific cancers. However, comprehensive research on CEP55 is lacking in pan-cancer. METHODS: In-house and multi-center samples (n = 15,823) were used to analyze CEP55 in 33 cancers. The variance of CEP55 expression levels among tumor and control groups was evaluated by the Wilcoxon rank-sum test and standardized mean difference (SMD). The clinical value of CEP55 in cancers was assessed using receiver operating characteristic (ROC) curves, Cox regression analysis, and Kaplan-Meier curves. The correlations between CEP55 expression and the immune microenvironment were explored using Spearman's correlation coefficient. RESULTS: The data of clustered regularly interspaced short palindromic repeats confirmed that CEP55 was essential for the survival of cancer cells in multiple cancer types. Elevated CEP55 mRNA expression was observed in 20 cancers, including glioblastoma multiforme (p < 0.05). CEP55 mRNA expression made it feasible to distinguish 21 cancer types between cancer specimens and their control samples (AUC = 0.97), indicating the potential of CEP55 for predicting cancer status. Overexpression of CEP55 was correlated with the prognosis of cancer individuals for 18 cancer types, exhibiting its prognostic value. CEP55 expression was relevant to tumor mutation burden, microsatellite instability, neoantigen counts, and the immune microenvironment in various cancers (p < 0.05). The expression level and clinical relevance of CEP55 in cancers were verified in lung squamous cell carcinoma using in-house and multi-center samples (SMD = 4.07; AUC > 0.95; p < 0.05). CONCLUSION: CEP55 may be an immune-related predictive and prognostic marker for multiple cancers, including lung squamous cell carcinoma.

Metagenomic Next-Generation Sequencing Assists in the Diagnosis of Mediastinal Aspergillus fumigatus Abscess in an Immunocompetent Patient: A Case Report and Literature Review.

Background: Aspergillus fumigatus is an opportunistic fungal pathogen, which is commonly found in lungs and rarely causes infections in mediastinum. Mediastinal Aspergillus abscess is a serious infectious condition, and is characterized by difficult diagnosis due to its clinical manifestations being nonspecific. Case Presentation: Here, we report a case of a mediastinal Aspergillus fumigatus abscess in an immunocompetent patient. The patient was a 45-year-old woman who presented with a 20-day history of sore throat without any underlying diseases. Chest computed tomography (CT) showed a mass in the anterior superior mediastinum. Metagenomic next-generation sequencing (mNGS) identified Aspergillus fumigatus sequences in endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) tissue, indicating the mediastinal Aspergillus fumigatus infection of this patient. The following mediastinal biopsy histological analysis and tissue fungi culture also suggested Aspergillus fumigatus infection, confirming the mNGS detection. The patient was diagnosed with mediastinal aspergillosis caused by Aspergillus fumigatus. After timely voriconazole treatment, the patient was discharged with good condition. Conclusion: Our study presented a rare case with mediastinal Aspergillus fumigatus abscess in an immunocompetent patient. As a new clinical diagnostic method, mNGS could assist timely diagnosis and precise treatment of Aspergillus infection.

The clinical significance and mechanism of microRNA-22-3p targeting TP53 in lung adenocarcinoma.

BACKGROUND: At present, studies on MircoRNA-22-3p (miR-22-3p) in lung adenocarcinoma use a single method, lack multi-center validation and multi-method validation, and there is no big data concept to predict and validate target genes. OBJECTIVE: To investigate the expression, potential targets and clinicopathological significance of miR-22-3p in lung adenocarcinoma (LUAD) tissues. METHODS: LUAD formalin-fixed paraffin-embedded (FFPE) tumors and adjacent normal lung tissues were collected for real-time quantitative polymerase chain reaction (RT-qPCR). Collect miR-22-3p in LUAD and non-cancer lung tissue from high-throughput datasets, standardized mean difference (SMD) and area under the curve (AUC) of the comprehensive receiver operating curve (summary receiver operating characteristic cure, sROC curve) were calculated. Cell function experiments on A549 cells transfected with LV-hsa-miR-22-3p. Target genes were predicted by the miRwalk2.0 website and the resulting target genes were subjected to Gene Ontology (GO) pathway enrichment analysis and constructed to protein-protein interaction network. Finally, the protein expression level of the key gene TP53 was validated by searching The Human Protein Atlas (THPA) database to incorporate TP53 immunohistochemical results in LUAD. RESULTS: RT-qPCR result from 41 pairs of LUAD and adjacent lung tissues showed that miR-22-3p was downregulated in LUAD (AUC = 0.6597, p= 0.0128). Globally, a total of 838 LUADs and 494 non-cancerous lung tissues were included, and were finally combined into 14 platforms. Compared with noncancerous tissue, miR-22-3p expression level was significantly reduced in LUAD tissue (SMD =-0.32, AUC = 0.72l); cell function experiments showed that miR-22-3p has inhibitory effects on cell proliferation, migration and invasion, and has promotion effect on apoptosis. Moreover, target genes prediction, GO pathway enrichment analysis and PPI network exhibited TP53 as a key gene of target gene of miR-22-3p; at last, a total of 114 high-throughput datasets were included, including 3897 LUADs and 2993 non-cancerous lung tissues, and were finally combined into 37 platforms. Compared with noncancerous tissue, TP53 expression level was significantly increased in LUAD (SMD = 0.39, p< 0.01) and it was verified by the protein expression data from THPA. CONCLUSION: Overexpression of miR-22-3p may inhibit LUAD cell proliferation, migration and invasion through TP53, and promote cell apoptosis.

Prognostic Signature and Discrimination Signature of Lung Adenocarcinoma based on Pyroptosis-Related Genes.

BACKGROUND: The clinical value of pyroptosis-related genes (PRGs) in lung adenocarcinoma (LUAD) remains obscure. OBJECTIVE: The study attempts to explore PRGs in LUAD, which will enable an understanding of LUAD from the perspective of PRGs. METHODS: Lung adenocarcinoma patients were diagnosed using pathology, and their clinical information was collected from several public databases. A PRGs prognostic signature (PPS) for LUAD patients was established based on a multivariate Cox regression analysis. The differential expression of PRGs was identified using standardized mean differences in 6,958 samples. The area under the curve (AUC) was used to evaluate the predictive effects of the PPS to determine the survival rate of LUAD patients. Decision curve analysis was utilized to assess the clinical significance of the PPS in LUAD. RESULTS: The PPS consists of five PRGs, namely CASP3, CASP9, GSDMB, NLRP1, and TNF. The prognostic effect of the PPS is evident in all the predicted one-, three-, and five-year survival rates (AUCs ≥ 0.58). The PPS represents an independent risk factor for the prognosis of LUAD patients (hazard ratio > 1; 95% confidence interval excluding 1). The PPS risk score can predict the prognosis of LUAD patients more accurately than PRGs of the PPS and multiple clinical parameters, such as age, tumor stage, and clinical stage. The decision curve analysis revealed that the nomogram based on the PPS and clinical parameters might result in better clinical decisions. CONCLUSION: The PPS makes it feasible to distinguish LUAD from non-LUAD. Thus, the underlying significance of the PPS in distinguishing LUAD from non-LUAD is promising.

The Clinical Features and Management of Empyema Caused by Streptococcus constellatus.

Background: Streptococcus constellatus, a commensal, plays an important role in purulent infections. It has been reported as aggressive pathogen causing pleural empyema. But the role of S. constellatus in empyema has not been taken seriously. There are no studies about clinical characteristics of empyema caused by S. constellatus domestically and abroad. This study aimed to explore the clinical features and management of empyema caused by S. constellatus. Methods: A retrospective review of 9 patients diagnosed with empyema caused by S. constellatus in a hospital between January 2010 and August 2021 was performed. Results: S. constellatus empyema were mostly seen in old males (66.7%) with comorbid diseases. The high-risk factors include diabetes mellitus, oral infection, and oral surgery. All were unilateral encapsulated empyema (right-side, 55.6%), diagnosed with pneumonia (bilateral pneumonia, 88.9%; ipsilateral lung abscess, 44.4%). 33.3% of patients had S. constellatus and anaerobes co-isolated. S. constellatus were sensitive to penicillin G, linezolid, levofloxacin, vancomycin, ceftriaxone, and chloramphenicol, resistant to erythromycin, tetracycline, and clindamycin. 33.3% of the patients needed ventilator support. The primary treatment to S. constellatus empyema was timely pus drainage, intravenous antibiotics, and enough nutrition support, intrapleural fibrinolytics and surgery (VAST recommended first) in necessity. Conclusion: S. constellatus may cause pneumonia and lung abscess first and then spread to cause empyema mainly in old males with comorbid diseases. S. constellatus often co-isolated with anaerobes in empyema. Antibiotics should cover simultaneously both S. constellatus and anaerobes.

Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: Combination treatment with erlotinib plus bevacizumab has the potential to become a standard treatment regimen for patients with epidermal growth factor receptor mutation-positive (EGFRm+) advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy and safety of erlotinib plus bevacizumab in patients with EGFRm+ advanced NSCLC. DESIGN: Systematic review and meta-analysis. DATA SOURCES: The PubMed, Embase, Web of Science and Cochrane Library databases were searched, from inception to 15 January 2022. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs), reported in English, assessing the efficacy of erlotinib plus bevacizumab versus erlotinib monotherapy in patients with EGFRm + advanced NSCLC. DATA EXTRACTION AND SYNTHESIS: The main objective was to assess overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse events (AEs). Two independent reviewers extracted data and assessed the risk of bias. A random-effects model was used where there was evidence for homogeneous effects. RESULTS: Four RCTs (reported across six publications) were included in the meta-analysis, with a total of 775 patients included in the pooled analyses of PFS, OS and ORR (387 in the erlotinib plus bevacizumab intervention group and 388 in the erlotinib group). Compared with the erlotinib alone group, the erlotinib plus bevacizumab group achieved a significantly prolonged PFS (HR: 0.59; 95% CI 0.49 to 0.72; p<0.00001; I2=0%), but OS (HR: 0.95; 95% CI 0.78 to 1.15; p=0.59; I2=0%) and ORR (OR: 1.25; 95% CI 0.89 to 1.74; p=0.19; I2=0%) were not significantly prolonged. A total of 776 cases were used for a pooled analysis of AEs. Regarding AEs, combined treatment significantly increased the incidence of diarrhoea (51% vs 43%, 95% CI 1.03 to 1.38; p=0.006), haemorrhagic events (41% vs 20%, 95% CI 1.12 to 6.31; p=0.03), proteinuria (25% vs 3%, 95% CI 4.86 to 17.66; p<0.0001) and hypertension (40% vs 8%, 95% CI 3.66 to 7.88; p<0.0001). CONCLUSIONS: Erlotinib plus bevacizumab for the treatment of patients with EGFRm+ advanced NSCLC was associated with significantly prolonged PFS compared with erlotinib alone, but the combination did not prolong OS.

The clinical significance of integrin subunit alpha V in cancers: from small cell lung carcinoma to pan-cancer.

BACKGROUND: Little is known about the relationship between integrin subunit alpha V (ITGAV) and cancers, including small cell lung cancer (SCLC). METHODS: Using large sample size from multiple sources, the clinical roles of ITGAV expression in SCLC were explored using differential expression analysis, receiver operating characteristic curves, Kaplan-Meier curves, etc. RESULTS: Decreased mRNA (SMD = - 1.05) and increased protein levels of ITGAV were detected in SCLC (n = 865). Transcription factors-ZEB2, IK2F1, and EGR2-may regulate ITGAV expression in SCLC, as they had ChIP-Seq (chromatin immunoprecipitation followed by sequencing) peaks upstream of the transcription start site of ITGAV. ITGAV expression made it feasible to distinguish SCLC from non-SCLC (AUC = 0.88, sensitivity = 0.78, specificity = 0.84), and represented a risk role in the prognosis of SCLC (p < 0.05). ITGAV may play a role in cancers by influencing several immunity-related signaling pathways and immune cells. Further, the extensive pan-cancer analysis verified the differential expression of ITGAV and its clinical significance in multiple cancers. CONCLUSION: ITGAV served as a potential marker for prognosis and identification of cancers including SCLC.

Epidermal growth factor receptor mutation p.A864V in small cell lung cancer and lung squamous cell carcinoma: a case report and review of literature.

Mutations in the epidermal growth factor receptor ( EGFR ) have been identified in 10-20% of nonsmall cell lung cancer (NSCLC), specifically lung adenocarcinomas. However, these mutations have rarely been reported in small cell lung cancer (SCLC) and lung squamous cell carcinoma (LUSC). Treatment for SCLC and LUSC patients has not yet been established. We present a rare case of p.A864V mutation in Exon 21 of EGFR gene in a patient with both SCLC and LUSC, which is the first case of such mutation type in lung cancer in the world. The patient was a 55-year-old female nonsmoker with stage IV SCLC and LUSC, gene sequencing revealed EGFR gene mutation, she refused EGFR tyrosine kinase inhibitors (TKIs) targeted therapy and received conservative treatment, which led to disease progression. In conclusion, clinicians should be aware of the possibility of the rare EGFR mutations. Platinum-based chemotherapy can be treated for SCLC and LUSC patients.

Clinical significance of cyclin-dependent kinase inhibitor 2C expression in cancers: from small cell lung carcinoma to pan-cancers.

BACKGROUND: Cyclin-dependent kinase inhibitor 2C (CDKN2C) was identified to participate in the occurrence and development of multiple cancers; however, its roles in small cell lung carcinoma (SCLC) remain unclear. METHODS: Differential expression analysis of CDKN2C between SCLC and non-SCLC were performed based on 937 samples from multiple centers. The prognosis effects of CDKN2C in patients with SCLC were detected using both Kaplan-Meier curves and log-rank tests. Using receiver-operating characteristic curves, whether CDKN2C expression made it feasible to distinguish SCLC was determined. The potential mechanisms of CDKN2C in SCLC were investigated by gene ontology terms and signaling pathways (Kyoto Encyclopedia of Genes and Genomes). Based on 10,080 samples, a pan-cancer analysis was also performed to determine the roles of CDKN2C in multiple cancers. RESULTS: For the first time, upregulated CDKN2C expression was detected in SCLC samples at both the mRNA and protein levels (p of Wilcoxon rank-sum test < 0.05; standardized mean difference = 2.86 [95% CI 2.20-3.52]). Transcription factor FOXA1 expression may positively regulate CDKN2C expression levels in SCLC. High CDKN2C expression levels were related to the poor prognosis of patients with SCLC (hazard ratio > 1, p < 0.05) and showed pronounced effects for distinguishing SCLC from non-SCLC (sensitivity, specificity, and area under the curve ≥ 0.95). CDKN2C expression may play a role in the development of SCLC by affecting the cell cycle. Furthermore, the first pan-cancer analysis revealed the differential expression of CDKN2C in 16 cancers (breast invasive carcinoma, etc.) and its independent prognostic significance in nine cancers (e.g., adrenocortical carcinoma). CDKN2C expression was related to the immune microenvironment, suggesting its potential usefulness as a prognostic marker in immunotherapy. CONCLUSIONS: This study identified upregulated CDKN2C expression and its clinical significance in SCLC and other multiple cancers, suggesting its potential usefulness as a biomarker in treating and differentiating cancers.

SYNJ2 is a novel and potential biomarker for the prediction and treatment of cancers: from lung squamous cell carcinoma to pan-cancer.

BACKGROUND: The roles and clinical values of synaptojanin 2 (SYNJ2) in lung squamous cell carcinoma (LUSC) remain unclear. METHODS: A total of 2824 samples from multi-center were collected to identify the expression of SYNJ2 in LUSC by using Wilcoxon rank-sum test, t-test, and standardized mean difference (SMD), and 194 in-house samples were also included to validate SYNJ2 expression in LUSC. The clinical roles of SYNJ2 were investigated via receiver operating characteristic (ROC) curves, univariate Cox regression analysis, and Kaplan-Meier plots. The underlying mechanisms of SYNJ2 in LUSC were explored by gene set enrichment analysis and immune correlation analysis. Further, a pan-cancer analysis based on 10,238 sapiens was performed to promote the understating of the expression and clinical significance of SYNJ2 in multiple human cancers. RESULTS: SYNJ2 was found to be significantly upregulated in LUSC at both mRNA and protein levels (p < 0.05, SMD = 0.89 [95% CI 0.34-1.45]) via public and in-house samples. Overexpressed SYNJ2 predicted poor prognosis for LUSC patients (hazard ratio = 2.38 [95% CI 1.42-3.98]). The cancer-promoting effect of SYNJ2 may be related to protein digestion and absorption and extracellular matrix-receptor interaction. SYNJ2 expression was closely related to immune cell infiltration, indicating its role in the immune response. Moreover, the distinct expression levels and essential clinical relevance of SYNJ2 in a series of cancers were initially revealed in this study. CONCLUSIONS: This study disclosed the clinical significance of SYNJ2 in LUSC and multiple cancers, demonstrating the novel and potential biomarker for predicting and treating cancers.

Expression Landscape and Functional Roles of HOXA4 and HOXA5 in Lung Adenocarcinoma.

BACKGROUND: The role of HOXA family genes in the occurrence and progression of a variety of human cancers has been scatteredly reported. However, there is no systematic study on the differential expression, prognostic significance and potential molecular mechanism of HOXA4 and HOXA5 in LUAD. METHODS: In-house immunohistochemistry (IHC), multi-center microarrays, RT-qPCR and RNA-seq data were incorporated for comprehensively evaluating the expression and prognostic value of HOXA4 and HOXA5 in LUAD. The mechanism of HOXA4 and HOXA5 in the formation and development of LUAD was analyzed from multiple aspects of immune correlations, upstream transcriptional regulation, functional states of single cells and co-expressed gene network. The functional roles of HOXA4 and HOXA5 in LUAD were validated by in vitro experiments. RESULTS: As a result, in 3201 LUAD samples and 2494 non-cancer lung samples, HOXA4 and HOXA5 were significantly downexpressed (P < 0.05). The aberrant expression of HOXA5 was significantly correlated with the clinical progression of LUAD (P < 0.05). HOXA5 showed remarkable prognostic value for LUAD patients (P < 0.05). The expression of HOXA4 and HOXA5 in LUAD were negatively correlated with tumor purity and positively correlated with the infiltration of various immune cells such as B cells, T cells and macrophages. HOXA4 and HOXA5 overexpression had notable inhibitory effect on the proliferation, migration and invasion of LUAD cells. CONCLUSIONS: In conclusion, the identified downexpressed HOXA4 and HOXA5 had significant distinguishing ability for LUAD samples and affected the cellular functions of LUAD cells. The low expression of HOXA5 indicated worse overall survival of LUAD patients. Therefore, the two HOXA family genes especially HOXA5 may serve as potential biomarkers for LUAD.

Ogt Demonstrated Conspicuous Clinical Significance in Cancers, from Pan-Cancer to Small-Cell Lung Cancer.

The clinical progression of small-cell lung cancer (SCLC) remains pessimistic. The aim of the present study was to promote the understanding of the clinical significance and mechanism of O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) in SCLC. Wilcoxon tests, standardized mean difference (SMD), and Kruskal-Wallis tests were utilized to compare OGT level differences among the experimental and control groups. The univariate Cox regression analysis, Kaplan-Meier curves, and receiver operating characteristic curves were applied to determine OGT's clinical relevance in cancers. The Spearman correlation analysis and enrichment analysis were utilized to explore the underlying mechanisms of OGT in cancers. For the first time in the field, we provide an overview of OGT in 32 cancers using a large number of samples (n = 21,196), determining distinct OGT expression in 25 cancers and its prognosis effects in 12 cancers. Furthermore, using 950 samples from multiple sources, upregulated OGT was found in both mRNA and protein levels in SCLC (SMD = 0.93, 95% CI [0.24, 1.63]). Higher OGT levels represented a more unfavorable disease-free interval for SCLC patients (p < 0.001). The research also identified OGT expression as a potential marker for SCLC prediction (sensitivity = 0.79, specificity = 0.86, and AUC = 0.88). The high expression of OGT in SCLC may result from the positive regulation of two transcription factors-DEK and XRN2. We primarily investigated the underlying mechanisms of OGT in SCLC. Herein, based on the analyses from pan-cancer to SCLC, OGT demonstrated conspicuous clinical significance. OGT may be an underlying biomarker for the treatment and identification of some cancers, including SCLC.

Identification of the susceptibility genes for COVID-19 in lung adenocarcinoma with global data and biological computation methods.

INTRODUCTION: The risk of infection with COVID-19 is high in lung adenocarcinoma (LUAD) patients, and there is a dearth of studies on the molecular mechanism underlying the high susceptibility of LUAD patients to COVID-19 from the perspective of the global differential expression landscape. OBJECTIVES: To fill the research void on the molecular mechanism underlying the high susceptibility of LUAD patients to COVID-19 from the perspective of the global differential expression landscape. METHODS: Herein, we identified genes, specifically the differentially expressed genes (DEGs), correlated with the susceptibility of LUAD patients to COVID-19. These were obtained by calculating standard mean deviation (SMD) values for 49 SARS-CoV-2-infected LUAD samples and 24 non-affected LUAD samples, as well as 3931 LUAD samples and 3027 non-cancer lung samples from 40 pooled RNA-seq and microarray datasets. Hub susceptibility genes significantly related to COVID-19 were further selected by weighted gene co-expression network analysis. Then, the hub genes were further analyzed via an examination of their clinical significance in multiple datasets, a correlation analysis of the immune cell infiltration level, and their interactions with the interactome sets of the A549 cell line. RESULTS: A total of 257 susceptibility genes were identified, and these genes were associated with RNA splicing, mitochondrial functions, and proteasomes. Ten genes, MEA1, MRPL24, PPIH, EBNA1BP2, MRTO4, RABEPK, TRMT112, PFDN2, PFDN6, and NDUFS3, were confirmed to be the hub susceptibility genes for COVID-19 in LUAD patients, and the hub susceptibility genes were significantly correlated with the infiltration of multiple immune cells. CONCLUSION: In conclusion, the susceptibility genes for COVID-19 in LUAD patients discovered in this study may increase our understanding of the high risk of COVID-19 in LUAD patients.

The Indication of Poor Prognosis by High Expression of ENO1 in Squamous Cell Carcinoma of the Lung.

The purpose of this study is to investigate the significance of alpha-enolase (ENO1) expression in squamous cell carcinoma of the lung (LUSC), its prognostic value, and prospective molecular mechanism. Using multiplatforms data, including in-house immunohistochemistry, in-house real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), in-house microarray, and public high-throughput data, the expression significance and prognostic role of ENO1 in LUSC tissues were analyzed comprehensively. With the combination of all eligible cases, compared with 941 non-LUSC lung tissues, ENO1 was significantly overexpressed in 1163 cases of LUSC (standardized mean difference (SMD) = 1.23, 95% confidence interval (CI) = 0.76-1.70, P < 0.001). ENO1 also displayed a great ability to differentiate LUSC tissues from non-LUSC lung tissues (AUC = 0.8705) with the comprehensive sensitivity being 0.88 [0.83-0.92], and comprehensive specificity being 0.89 [0.84-0.94]). Moreover, in 1860 cases of LUSC with survival information, patients with higher expression of ENO1 had poorer prognosis (hazard ratio (HR) = 1.20, 95% CI = 1.01-1.43, P = 0.043). ENO1 and its related genes mainly participated in the pathways of cell division and proliferation. In conclusion, the upregulation of ENO1 could affect the carcinogenesis and unfavorable outcome of LUSC.