H3K4me3-related lncRNAs signature and comprehensive analysis of H3K4me3 regulating tumor immunity in lung adenocarcinoma.

BACKGROUD: The role of epigenetic modifications in tumorigenesis has been widely reported. However, the role and mechanism of H3K4me3 modification in lung adenocarcinoma (LUAD) are rarely reported systematically. We, therefore, sought to analyze the characteristics of LUAD associated with H3K4me3 modification, build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD and clarify the potential value of H3K4me3 in immunotherapy of LUAD. METHODS: We evaluated H3K4me3-lncRNA patterns and H3K4me3-lncRNA scores of 477 LUAD samples based on 53 lncRNAs closely correlated to H3K4me3 regulators and comprehensive analyzed the role of these patterns in tumorigenesis and tumor immunity. Using Gene set variation analysis (GSVA), we systematically evaluated the H3K4me3 level of every sample and deeply analyzed the effect of H3K4me3 on the prognosis of LUAD. In addition, we included two independent immunotherapy cohorts to study the impact of high H3K4me3 score on the prognosis of patients. We also used an independent cohort with 52 matched paraffin specimens of LUAD to verify the impact of high H3K3me3 expression on the prognosis of patients. RESULTS: We identified three H3K4me3-lncRNA patterns that exhibited specific immune characteristics. Characterized by immunosuppressive and increased TGFß-mediated epithelial-mesenchymal transition (EMT), patients with high H3K4me3-lncRNA score had a poor overall survival and decreased H3K4me3 score. H3K4me3 score was significantly positively correlated with CD4+T-cell and CD8+T-cell activation, programmed cell death and immune checkpoints (ICs) expression, and was negatively correlated with MYC pathway, TP53 pathway, and cell proliferation. Patients with high H3K4me3 score showed elevated expression of ICs, potentiated CD4 T-cell and CD8 T-cell activation, increased programmed cell death, and suppressed cell proliferation and TGFß-mediated EMT. Patients with high H3K4me3 score and high expression of CTLA4, ICOS, TIGIT, PDCD1LG2, IDO1, CD274, PDCD1, LAG3, or HAVCR2 had the best survival advantage. Two independent immunotherapy cohorts verified that patients with high H3K4me3 score showed an increased inflamed tumor microenvironment (TME) phenotype and enhanced anti-PD-1/L1 immunotherapy response. Immunohistochemistry (IHC) data from 52 matched paraffin specimens of LUAD confirmed that the protein level of H3K4me3 in tumor was significantly lower than that of paracancerous tissues and H3K4me3 brought significant survival benefits to patients with LUAD. CONCLUSIONS: We build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD. More importantly, this study revealed characteristics of H3K4me3 modification in LUAD and clarified the important potential role of H3K4me3 on tumor immunotherapy and patients' survival.

Optimal targeting of sympathetic chain levels for treatment of palmar hyperhidrosis: an updated systematic review.

BACKGROUND: Palmar hyperhidrosis involves excessive sweating of the palms, with no known etiology. Endoscopic thoracic sympathectomy (ETS) is a safe and effective treatment for palmar hyperhidrosis, but compensatory hyperhidrosis is a common complication after ETS, leading to reduced patient satisfaction and postoperative quality of life. However, the appropriate level of the sympathetic chain to target with ETS to achieve maximum efficacy and reduce the risk of compensatory hyperhidrosis (CH) is controversial. In this systemic review, we investigated the appropriate level of sympathectomy for palmar hyperhidrosis. METHODS: PRISMA guidelines were implemented to complete a systematic review. We performed a computerized systematic literature search using PubMed and EMBASE from January 1990 to July 2016. We chose the Cochrane Collaboration's tool and the methodological index for non-randomized studies tool for examining study bias. RESULTS: A total of 4075 citations were identified, of which 91 were eligible for inclusion, including 68 observational studies and 23 comparative trials. In observational studies, sympathectomies showed similar efficacies for curing PH at different levels. However, T2-free groups (i.e., at levels T3, T4, or T3-T4 combined) could render a lower risk of Horner's syndrome (0 vs. 1.21 ± 0.49%, p = 0.036) and CH (28.75 ± 7.25 vs. 57.46 ± 3.86, p = 0.002) compared with T2 involved. In comparative trials, there were 12 studies describing the comparison between T2-free ETS and T2 involved, and 9 of 12 (75%) showed T2-free ETS could reduce the incidence of CH. Overall, lowering the level and limiting the extent of sympathectomy could reduce the incidence of complications. CONCLUSIONS: Cumulative data from more than 13,000 patients suggest that ETS is a safe, effective, and reproducible procedure with a high degree of patient satisfaction. Currently available evidence suggests that T2-free ETS may reduce the incidence of compensatory hyperhidrosis without compromising success rates and safety.

Prognostic prediction and comparison of three staging programs for patients with advanced (T2-T4) esophageal squamous carcinoma after radical resection.

Purpose: Lymph node-based staging protocols are frequently employed to evaluate the prognosis of esophageal cancer, yet their accuracy remains contentious. The present study was conducted to assess the prognostic significance of three lymph node staging systems, namely N stage, lymph node rate (LNR), and log odds of positive lymph nodes (LODDS), in patients diagnosed with advanced (T2-T4) esophageal squamous cell carcinoma (ESCC). Methods: This cohort comprised 319 eligible patients, with an additional 409 individuals retrieved from the Surveillance, Epidemiology, and End Results (SEER) database, forming the validation cohort. Differences in overall survival (OS) of patients between groups were assessed using the log-rank test. Prognostic independent risk variables were identified, and lymph nodes (LN) prognostic models were built using multivariate Cox regression analysis. Besides, the predictive accuracy of each model was evaluated utilizing the (-2) log-likelihood ratio (-2LLR), the likelihood ratio χ2 score (LRχ2), the Akaike information criterion (AIC), and Harrell's concordance index (C-index). To further evaluate the potential superiority of the model, a nomogram was constructed for comparison with the conventional Tumor Node Metastasis (TNM) staging approach. Results: Independent prognostic factors for advanced ESCC include the N stage, LNR, and LODDS. Herein, LODDS presented higher values for C-index and LRχ2, and lower values for AIC and -2LLR in OS compared to the others. Consequently, a nomogram was constructed based on LODDS. Calibration curves exhibited strong agreement, and assessment through C-index, receiver operating characteristic (ROC) curves, and clinical decision curve analysis (DCA) demonstrated promising clinical applicability. Conclusion: LODDS emerges as a promising future prognostic indicator. After surgery, the proposed model holds the potential to provide valuable treatment recommendations for patients with advanced ESCC.

Treatment and survival analysis for 40-year SEER data on upper esophageal cancer.

Background: Upper esophageal cancer (UEC) is rare in both Eastern and Western countries. The epidemiological characteristics and long-term survival of UEC patients are less known. In addition, the choice of optimal treatment for UEC has been controversial. Methods: Cases of UEC (C15.3 and C15.0) arising during the period from 1973 to 2013 were identified and selected using the SEER database. Student's t-test and Pearson's chi-square test were used to compare the differences in parameters among different groups. Esophageal cancer-specific survival (ECSS) and overall survival (OS) rates were calculated by using the Kaplan-Meier method. Cox proportional hazard regression was used to analyze predictive factors. Results: In the past 40 years, the cases of UEC have gradually increased, and the proportion of adenocarcinoma (AD) has gradually increased (from 3.6% to 11.8%, p < 0.001). There has been a significant increase (1973-1982 vs. 2004-2013) in median OS (7 months vs. 10 months, p < 0.001) and median ECSS (7 months vs. 11 months, p < 0.001) among UEC patients from 1973 to 2013. For the impact of different treatments, the results showed that the ECSS and OS of surgery without radiation (SWR) and radiation plus surgery (R+S) were superior to those of radiation without surgery (RWS). Subgroup analysis showed that ECSS and OS were highest among patients treated with SWR compared with R+S and RWS for patients with localized disease. For regional disease, ECSS and OS were highest among patients with R+S compared with SWR or RWS. Among patients with regional-stage squamous cell carcinoma (SCC), OS was higher with neoadjuvant radiotherapy or adjuvant radiotherapy compared with SWR. Multivariate analysis showed that radiotherapy sequence was dependently associated with OS among patients with regional-stage SCC. Conclusion: Although the long-term survival of UEC remains poor, it has gradually increased since 1973. This should be closely related to the improvement of medical care over the past 40 years. Different treatment methods have a great influence on the long-term survival of UEC. For localized diseases, surgery may be a better choice. For regional disease, surgery plus adjuvant or neoadjuvant radiotherapy may be more beneficial to improve the long-term prognosis of UEC patients.

Circ-GSK3B up-regulates GSK3B to suppress the progression of lung adenocarcinoma.

GSK3B is the mRNA form of glycogen synthase kinase 3 beta (GSK-3ß), which is a critical repressor of Wnt/ß-catenin signaling pathway and generally inhibited in cancer cells. Plenty of researches have disclosed that circular RNAs, namely circRNAs exert important functions in the progression of various human malignancies including lung adenocarcinoma (LUAD). Therefore, we attempted to explore whether there existed certain circRNAs that could mediate LUAD development by regulating GSK3B expression and Wnt/ß-catenin pathway. In the present research, circ-GSK3B (hsa_circ_0066903) was found to be significantly down-regulated in LUAD tissues and cells and it suppressed the proliferation, migration and stemness of LUAD cells. Furthermore, it was discovered that circ-GSK3B competitively sponged miR-3681-3p and miR-3909 to elevate GSK3B expression. Circ-GSK3B could impair the binding ability of FKBP51 to GSK-3ß to inhibit the phosphorylation of GSK-3ßS9, resulting in the inactivation of Wnt/ß-catenin signaling. In addition, the regulatory effect of circ-GSK3B on LUAD tumorigenesis and cell progression was testified through in vitro and in vivo rescue experiments. In conclusion, circ-GSK3B suppressed LUAD development through up-regulating and activating GSK3B.

Corrigendum: Clinical Significance and Immunometabolism Landscapes of a Novel Recurrence-Associated Lipid Metabolism Signature In Early-Stage Lung Adenocarcinoma: A Comprehensive Analysis.

[This corrects the article DOI: 10.3389/fimmu.2022.783495.].

Clinical Significance and Immunometabolism Landscapes of a Novel Recurrence-Associated Lipid Metabolism Signature In Early-Stage Lung Adenocarcinoma: A Comprehensive Analysis.

Background: The early-stage lung adenocarcinoma (LUAD) incidence has increased with heightened public awareness and lung cancer screening implementation. Lipid metabolism abnormalities are associated with lung cancer initiation and progression. However, the comprehensive features and clinical significance of the immunometabolism landscape and lipid metabolism-related genes (LMRGs) in cancer recurrence for early-stage LUAD remain obscure. Methods: LMRGs were extracted from Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Samples from The Cancer Genome Atlas (TCGA) were used as training cohort, and samples from four Gene Expression Omnibus (GEO) datasets were used as validation cohorts. The LUAD recurrence-associated LMRG molecular pattern and signature was constructed through unsupervised consensus clustering, time-dependent receiver operating characteristic (ROC), and least absolute shrinkage and selection operator (LASSO) analyses. Kaplan-Meier, ROC, and multivariate Cox regression analyses and prognostic meta-analysis were used to test the suitability and stability of the signature. We used Gene Ontology (GO), KEGG pathway, immune cell infiltration, chemotherapy response analyses, gene set variation analysis (GSVA), and GSEA to explore molecular mechanisms and immune landscapes related to the signature and the potential of the signature to predict immunotherapy or chemotherapy response. Results: First, two LMRG molecular patterns were established, which showed diverse prognoses and immune infiltration statuses. Then, a 12-gene signature was identified, and a risk model was built. The signature remained an independent prognostic parameter in multivariate Cox regression and prognostic meta-analysis. In addition, this signature stratified patients into high- and low-risk groups with significantly different recurrence rates and was well validated in different clinical subgroups and several independent validation cohorts. The results of GO and KEGG analyses and GSEA showed that there were differences in multiple lipid metabolism, immune response, and drug metabolism pathways between the high- and low-risk groups. Further analyses revealed that the signature-based risk model was related to distinct immune cell proportions, immune checkpoint parameters, and immunotherapy and chemotherapy response, consistent with the GO, KEGG, and GSEA results. Conclusions: This is the first lipid metabolism-based signature for predicting recurrence, and it could provide vital guidance to achieve optimized antitumor for immunotherapy or chemotherapy for early-stage LUAD.

Immune profile of the tumor microenvironment and the identification of a four-gene signature for lung adenocarcinoma.

The composition and relative abundances of immune cells in the tumor microenvironment are key factors affecting the progression of lung adenocarcinomas (LUADs) and the efficacy of immunotherapy. Using the cancer gene expression dataset from The Cancer Genome Atlas (TCGA) program, we scored stromal and immune cells for tumor purity prediction by CIBERSORT and ESTMATE. Differential expression analysis was employed to identify 374 genes between the high-score group and the low-score group, which were utilized to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Protein-protein interaction (PPI) and Cox regression analysis were performed on the differentially expressed genes (DEGs) to identify four key tumor microenvironment (TME) -related genes (CCR2, CCR4, P2RY12, and P2RY13). The expression levels of the four DEGs differed significantly among LUAD patients of different ages, genders, and TNM stages. We found that the infiltration of resting memory CD4+ T cells, memory B cells, and M0 macrophages into the TME was co-regulated by these four DEGs. These four genes were closely related to the prognosis of LUAD and affected the infiltration of immune cells into the TME, which had predictive prognostic value in LUAD.

Could lung cancer exosomes induce apoptosis of natural killer cells through the p75NTR-proNGF-sortilin axis?

Lung cancer is the leading cause of cancer-related death worldwide. Tumor exosomes play an important role in the development of lung cancer. Previous studies indicated that tumor exosomes derived from lung cancer cells contained abundant sortilin. Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) family of receptors that act as co-receptors for p75NTR and play an independent role in cell death induced by proNGF. Recently, a study showed that proNGF could mediate the death of natural killer (NK) cells through binding to the p75NTR-sortilin complex. However, it has not been reported, to our knowledge, that lung cancer cells induce NK cell apoptosis through a p75NTR-proNGF-sortilin mechanism. As a secreted protein, lung cancer cells may release some proNGF into the tumor microenvironment. We therefore hypothesized that lung cancer cells may promote the apoptosis of NK cells through releasing exosomal sortilin and proNGF. To test this hypothesis, experiments involving the production of exosomal sortilin and proNGF in lung cancer cells and the expression of p75NTR in NK cells are required based upon previously established experiments using fluorescent components. Such experiments may provide insight into the potential mechanism by which lung cancer cells promote apoptosis of NK cells through a p75NTR-proNGF-sortilin pathway.