Comprehensive analysis of exosome gene LYPD3 and prognosis/immune cell infiltration in lung cancer.

Background: Lung cancer (LC) is a leading cause of cancer-associated mortality worldwide, with high incidence and mortality rates. Ly6/PLAUR domain containing 3 (LYPD3) is a tumorigenic and highly glycosylated cell surface protein that has been rarely reported in LC. This study aimed to explore the prognostic role and immune cell infiltration of LYPD3 in LC. Methods: We used ExoCarta, a database of exosomal proteins and RNA, to select exosomes in LC. The Tumor Immune Estimation Resource (TIMER) and Human Protein Atlas (HPA) databases were utilized to compare the expression of LYPD3 in LC. We applied Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Kaplan-Meier (KM) plotter to evaluate the prognostic prediction performance of LYPD3. Biological processes (BPs), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and gene set enrichment analysis (GSEA) analyses were performed to illustrate the possible role of LYPD3 in LC. The correlations between LYPD3 and immune cell infiltration were explored using Tumor and Immune System Interaction Database (TISIDB), GEPIA2, and TIMER. R software was used for statistical analysis and mapping. Results: A total of 904 exosome molecules were screened in LC. Further analysis showed that the up-regulation of LYPD3 in these 904 exosome molecules was associated with poor prognosis in LC. Pan-cancer analyses revealed that the expression of LYPD3 varied in many cancers, particularly in LC. Clinical correlation analysis indicated that LYPD3 was associated with stage and T classification in LC. We observed that LYPD3 co-expression genes were associated with cell cycle, DNA replication, proteasome, and regulation of the actin cytoskeleton by GSEA. Moreover, LYPD3 was associated with immune modulators. Immunophenoscores (IPS) and IPS-CTLA4 were significantly different between the high LYPD3 group and low LYPD3 group. Additionally, the median half maximal inhibitory concentration (IC50) of bexarotene, cyclopamine, etoposide, and paclitaxel in LYPD3 high group was significantly lower than that in LYPD3 low group. Conclusions: LYPD3 is involved in many BPs of LC, such as regulating immune cell infiltration and affecting prognosis. Therefore, LYPD3 may have potential value as a biomarker for prognosis and immunotherapy in LC.

Single-cell profiling of response to neoadjuvant chemo-immunotherapy in surgically resectable esophageal squamous cell carcinoma.

BACKGROUND: The efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within the tumor microenvironment (TME). Unveiling the immune landscape of ESCC in the context of NAT could shed light on heterogeneity and optimize therapeutic strategies for patients. METHODS: We analyzed single cells from 22 baseline and 24 post-NAT treatment samples of stage II/III ESCC patients to explore the association between the immune landscape and pathological response to neoadjuvant anti-PD-1 combination therapy, including pathological complete response (pCR), major pathological response (MPR), and incomplete pathological response (IPR). RESULTS: Single-cell profiling identified 14 major cell subsets of cancer, immune, and stromal cells. Trajectory analysis unveiled an interesting link between cancer cell differentiation and pathological response to NAT. ESCC tumors enriched with less differentiated cancer cells exhibited a potentially favorable pathological response to NAT, while tumors enriched with clusters of more differentiated cancer cells may resist treatment. Deconvolution of transcriptomes in pre-treatment tumors identified gene signatures in response to NAT contributed by specific immune cell populations. Upregulated genes associated with better pathological responses in CD8 + effector T cells primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, and negative regulation of the T cell apoptotic process, whereas downregulated genes were dominated by those in the immune response-activating cell surface receptor signaling pathway. Natural killer cells in pre-treatment tumors from pCR patients showed a similar upregulation of gene expression in response to IFNγ but a downregulation of genes in the neutrophil-mediated immunity pathways. A decreased cellular contexture of regulatory T cells in ESCC TME indicated a potentially favorable pathological response to NAT. Cell-cell communication analysis revealed extensive interactions between CCL5 and its receptor CCR5 in various immune cells of baseline pCR tumors. Immune checkpoint interaction pairs, including CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, and TNFSF4-TNFRSF4, might serve as additional therapeutic targets for ICI therapy in ESCC. CONCLUSIONS: This pioneering study unveiled an intriguing association between cancer cell differentiation and pathological response in esophageal cancer patients, revealing distinct subgroups of tumors for which neoadjuvant chemo-immunotherapy might be effective. We also delineated the immune landscape of ESCC tumors in the context of clinical response to NAT, which provides clinical insights for better understanding how patients respond to the treatment and further identifying novel therapeutic targets for ESCC patients in the future.

Circ-HSP90A expedites cell growth, stemness, and immune evasion in non-small cell lung cancer by regulating STAT3 signaling and PD-1/PD-L1 checkpoint.

BACKGROUND: Circular RNAs (circRNAs) are important participators in tumor progression for their stable structure and high tissue-specific expression. The purpose of this research was to clarify the potential and mechanism of a novel circRNA-circ-HSP90A in non-small cell lung cancer (NSCLC). METHODS: Biological potentials of circ-HSP90A in NSCLC were measured by functional assays. Molecular interaction was assessed by bioinformatics analysis and mechanical assays. RESULTS: Results depicted that circ-HSP90A was cyclization from its host gene heat shock protein 90 alpha (HSP90A) and was up-regulated in NSCLC cells. Circ-HSP90A depletion retarded proliferation, migration, invasion, and immune evasion. Mechanistically, circ-HSP90A recruited ubiquitin specific peptidase 30 (USP30) to stabilize HSP90A and then stimulated the signal transducer and activator of transcription 3 (STAT3) signaling. Meanwhile, circ-HSP90A sponged miR-424-5p to programmed cell death ligand 1 (PD-L1). CONCLUSIONS: Our study firstly showed that circ-HSP90A promoted cell growth, stemness, and immune evasion in NSCLC through regulating STAT3 signaling and programmed cell death 1 (PD-1)/PD-L1 checkpoint, mirroring that targeting circ-HSP90A might become a novel target of immunotherapy in NSCLC.

Machine Learning and Novel Biomarkers Associated with Immune Infiltration for the Diagnosis of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) accounts for the main esophageal cancer type, which is related to advanced stage and poor survivals. Therefore, novel diagnostic biomarkers are critically needed. In the current research, we aimed to screen novel diagnostic biomarkers based on machine learning. The expression profiles were obtained from GEO datasets (GSE20347, GSE38129, and GSE75241) and TCGA datasets. Differentially expressed genes (DEGs) were screened between 47 ESCC and 47 nontumor samples. The LASSO regression model and SVM-RFE analysis were carried out for the identification of potential markers. ROC analysis was carried out to assess discriminatory abilities. The expressions and diagnostic values of the candidates in ESCC were demonstrated in the GSE75241 datasets and TCGA datasets. We also explore the correlations between the critical genes and cancer immune infiltrates using CIBERSORT. In this study, we identified 27 DEGs in ESCC: 5 genes were significantly elevated, and 22 genes were significantly decreased. Based on the results of the SVM-RFE and LASSO regression model, we identified five potential diagnostic biomarkers for ESCC, including GPX3, COL11A1, EREG, MMP1, and MMP12. However, the diagnostic values of only GPX3, MMP1, and MMP12 were confirmed in GSE75241 datasets. Moreover, in TCGA datasets, we further confirmed that GPX3 expression was distinctly decreased in ESCC specimens, while the expression of MMP1 and MMP12 was noticeably increased in ESCC specimens. Immune cell infiltration analysis revealed that the expression of GPX3, MMP1, and MMP12 was associated with several immune, such as T cells CD8, macrophages M2, macrophages M0, and dendritic cells activated. Overall, our findings suggested GPX3, MMP1, and MMP12 as novel diagnostic marker and correlated with immune infiltrates in ESCC patients.

Evaluation of the Effect of Lymph Node Status on the Survival of Non-Small Cell Lung Cancer Patients With Brain Metastases: Applications of a Novel Grade Prognostic Assessment Score Model Involving N Stage.

BACKGROUND: Grade prognostic assessment (GPA) is widely used to evaluate the prognosis of non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This study aimed to investigate whether lymph node status (LNS) could be included as one of the GPA variables for NSCLC with BMs. METHODS: Overall, 586 patients with NSCLC and BMs were retrospectively analyzed. Overall survival stratified by LNS was analyzed using the Kaplan-Meier method. Multivariate analysis was also performed to identify independent prognostic factors using the Cox proportional hazards progression model. In the updated GPA index, prognostic factors and criteria of GPA score were weighted by effect magnitude relative risk (RR) and statistical significance. RESULTS: In NSCLC patients with BMs, those with lymph node involvement had worse overall survival (mOS, 13.4 months vs. 25.9 months, P <0.001) than those without lymph node involvement. Multivariate analysis showed that LNS might be an independent prognostic factor (RR: 1.702, CI: 1.340-2.162, P <0.001). Finally, five prognostic factors including LNS, the age of the patient, Karnofsky performance status (KPS), the number of BMs, and extracranial metastases were enrolled in our novel GPA index. With the updated GPA index involving the N stage, survival analysis was also performed. Prognostic results were significantly different among these four subgroups (Class A vs. Class B, P=0.047; Class B vs. Class C, P<0.001; Class C vs. Class D, P=0.007). CONCLUSIONS: These results indicate that LNS might be an indispensable prognostic factor in NSCLC with BM. The novel GPA model involving the N stage could provide more reliable evidence to estimate the survival of NSCLC patients with BMs.

[Analysis of clinical medication rules in 48 398 patients with limb fractures based on hospital information system].

To explore the clinical medication rules in the patients with limb fractures, and provide guidance for clinical practice. Data of 48 398 patients with limb fractures from 2001 to 2011 was extracted from the hospital information system(HIS) established by the institute of basic research in clinical medicine, China academy of Chinese medical sciences. The gender and age distribution of patients and clinical medication characteristics were described. Apriori algorithm was adopted to analyze the common drug combinations of Chinese medicine(CM) and western medicine(WM). The study results showed that the ratio of included males and females was 1.83∶1. There was a high peak of incidence for the patients from 18 to 44 years. Apriori algorithm showed that the usage of WM was more frequent than that of CM. The most commonly used CM was Lugua polypeptide and sodium aescinate injection. Blood-activating and stasis-resolving medicines, as well as tendons and bones-strengthening medicines were the commonly used CM types. In addition, WM antibiotics plus blood-activating and stasis-resolving CM, or antibiotics plus tendons and bones-strengthening CM was the most commonly used drug combination. Based on the analysis of available data, the prevalence of limb fracture was higher in men than in women; more in young and middle-aged patients; the common drug combination was antibiotics plus blood-activating and stasis-resolving CM, or antibiotics plus tendons and bones-strengthening CM. More prospective and high-quality clinical trials are necessary to evaluate the effect of CM or integrative medicine treatment for limb fracture in the future research.