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BackgroundLymphangiogenesis (LYM) has an important role in tumor progression and is strongly associated with tumor metastasis. However, the clinical application of LYM has not progressed as expected. The potential value of LYM needs to be further developed in lung adenocarcinoma (LUAD) patients.MethodsThe Sequencing data and clinical characteristics of LUAD patients were downloaded from The Cancer Genome Atlas and GEO databases. Multiple machine learning algorithms were used to screen feature genes and develop the LYM index. Immune cell infiltration, immune checkpoint expression, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and drug sensitivity analysis were used to explore the correlation of LYM index with immune profile and anti-tumor therapy.ResultsWe screened four lymphangiogenic feature genes (PECAM1, TIMP1, CXCL5 and PDGFB) to construct LYM index based on multiple machine learning algorithms. We divided LUAD patients into the high LYM index group and the low LYM index group based on the median LYM index. LYM index is a risk factor for the prognosis of LUAD patients. In addition, there was a significant difference in immune profile between high LYM index and low LYM index groups. LUAD patients in the low LYM index group seemed to benefit more from immunotherapy based on the results of TIDE algorithm.ConclusionOverall, we confirmed that the LYM index is a prognostic risk factor and a valuable predictor of immunotherapy response in LUAD patients, which provides new evidence for the potential application of LYM.

BackgroundPolyamine modification patterns in lung adenocarcinoma (LUAD) and their impact on prognosis, immune infiltration, and anti-tumor efficacy have not been systematically explored.MethodsPatients from The Cancer Genome Atlas (TCGA) were classified into subtypes according to polyamine metabolism-related genes using the consensus clustering method, and the survival outcomes and immune profile were compared. Meanwhile, the geneCluster was constructed according to the differentially expressed genes (DEGs) of the subtypes. Subsequently, the polyamine metabolism-related score (PMRS) system was established using the least absolute shrinkage and selection operator (LASSO) multivariate regression analysis in the TCGA training cohort (n = 245), which can be applied to characterize the prognosis. To verify the predictive performance of the PMRS, the internal cohort (n = 245) and the external cohort (n = 244) were recruited. The relationship between the PMRS and immune infiltration and antitumor responses was investigated.ResultsTwo distinct patterns (C1 and C2) were identified, in which the C1 subtype presented an adverse prognosis, high CD8+ T cell infiltration, tumor mutational burden (TMB), immune checkpoint, and low tumor immune dysfunction and exclusion (TIDE). Furthermore, two geneClusters were established, and similar findings were observed. The PMRS, including three genes (SMS, SMOX, and PSMC6), was then constructed to characterize the polyamine metabolic patterns, and the patients were divided into high- and low-PMRS groups. As confirmed by the validation cohort, the high-PMRS group possessed a poor prognosis. Moreover, external samples and immunohistochemistry confirmed that the three genes were highly expressed in tumor samples. Finally, immunotherapy and chemotherapy may be beneficial to the high-PMRS group based on the immunotherapy cohorts and low half-maximal inhibitory concentration (IC50) values.ConclusionWe identified distinct polyamine modification patterns and established a PMRS to provide new insights into the mechanism of polyamine action and improve the current anti-tumor strategy of LUAD.

BackgroundNowadays, the characteristics and treatment of combined small-cell lung carcinoma (CSCLC) remain controversial. This study aimed to analyze the features of clinical demographics, survival outcomes and treatment modalities among IV CSCLC, IV SCLC and IV NSCLC, to provide more evidence for the study of IV CSCLC.MethodsAll CSCLC, SCLC and NSCLC patient data were obtained from the SEER database (2010-2020). Pearson's χ2 test was used to compare the differences in clinical characteristics. Propensity score matching (PSM) was utilized to balance the bias of the variables between patients. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors. KM analysis was used to calculate survival. Adjusted analyses for the primary outcome of different treatment modalities of IV CSCLC, IV SCLC and IV NSCLC were performed using Cox regression models.ResultsA total of 493 patients with IV CSCLC, 35503 patients with SCLC, 122807 patients with IV NSCLC were included in this study. The demographic characteristics and tumor characteristics of the three groups were different. Before PSM, there were significant differences in OS and CSS among IV CSCLC, IV SCLC and IV NSCLC, After PSM, there was a significant difference in OS and CSS between the IV CSCLC and IV NSCLC. Risk/protective factors for OS and CSS were different in three groups. Chemotherapy, radiotherapy, and surgery can improve IV CSCLC's survival time. The combination of surgery and chemoradiotherapy treatment group for patients with IV CSCLC demonstrated best OS compared to control treatment groups, and the surgery combined chemotherapy treatment group exhibited the best CSS. Additionally, for select patients with stage IV CSCLC who have missed the window for surgical intervention at the time of initial diagnosis, chemoradiotherapy presents a viable and effective treatment option.ConclusionsThe clinical characteristics IV CSCLC, IV SCLC and IV NSCLC were significantly different. The prognosis for IV CSCLC is notably poorer than IV NSCLC, similar to IV SCLC. Surgery combined therapy emerged as the preferred treatment modalities and chemoradiotherapy was a good choice for patients who have lost the indication of surgery for patients diagnosed with IV CSCLC.

Background: Lung cancer has a high incidence and mortality rate worldwide. Vasculogenic mimicry (VM) is a specific modality of tumor angiogenesis that could potentially be a new target for tumor therapy. The purpose of this study was to explore the role of VM-related genes in assessing the prognosis and immune landscape of lung cancer.Methods: VM-related genes were obtained from previous studies, and the expression data and clinical data of lung adenocarcinoma (LUAD) patients were obtained from the TCGA database and GEO database. We performed enrichment analysis of 24 VM-related genes and screened hub genes by constructing a protein–protein interaction network and using Cytoscape software. Subsequently, we developed the VM score based on univariate Cox regression analysis and Lasso analysis and validated the VM score on the GSE72094 dataset. In addition, we constructed a nomogram based on the VM score in the TCGA cohort. Finally, we explored the correlation between the VM score and the tumor microenvironment, immune cell infiltration, immune checkpoints, and drug sensitivity.Results: Enrichment analysis revealed that VM-related genes were associated with the HIF signaling pathway and angiogenic pathway. We developed a VM score based on 3 genes (EPHA2, LAMC2 and LOXL2) in LUAD patients. Kaplan-Meier analysis showed that the VM score was associated with poor prognosis in LUAD patients. The receiver operating characteristic curve suggested that the VM score and nomogram are valid predictors for the overall survival of LUAD patients. The VM score was significantly correlated with immune cell infiltration, such as naïve B cells, neutrophils, and eosinophils, and there was a difference in the TME between the high VM score group and the low VM score group. LUAD patients in the high VM score group were more sensitive to antitumor drugs.Conclusion: In summary, the VM score developed in this study is a valuable indicator for evaluating the prognosis and immune landscape of LUAD patients. VM may be a potential target for antitumor therapy in lung cancer.

BackgroundLung adenocarcinoma (LUAD) is one of the most frequent causes of tumor-related mortality worldwide. Recently, the role of N7-methylguanosine (m7G) in tumors has begun to receive attention, but no investigation on the impact of m7G on LUAD. This study aims to elucidate the significance of m7G on the prognosis and immunotherapy in LUAD.MethodsConsensus clustering was employed to determine the molecular subtype according to m7G-related regulators extracted from The Cancer Genome Atlas (TCGA) database. Survival, clinicopathological features and tumor mutational burden (TMB) analysis were applied to research molecular characteristics of each subtype. Subsequently, “limma” package was used to screen differentially expressed genes (DEGs) between subtypes. In the TCGA train cohort (n = 245), a prognostic signature was established by univariate Cox regression, lasso regression and multivariate Cox regression analysis according to DEGs and survival analysis was employed to assess the prognosis. Then the prognostic value of the signature was verified by TCGA test cohort (n = 245), TCGA entire cohort (n = 490) and GSE31210 cohort (n = 226). Moreover, the association among immune infiltration, clinical features and the signature was investigated. The immune checkpoints, TMB and tumor immune dysfunction and exclusion (TIDE) were applied to predict the immunotherapy response.ResultsTwo novel molecular subtypes (C1 and C2) of LUAD were identified. Compared to C2 subtype, C1 subtype had poorer prognosis and higher TMB. Subsequently, the signature (called the “m7G score”) was constructed according to four key genes (E2F7, FAM83A, PITX3, and HOXA13). The distribution of m7G score were significantly different between two molecular subtypes. The patients with lower m7G score had better prognosis in TCGA train cohort and three verification cohort. The m7G score was intensively related to immune infiltration. Compared with the lower score, the higher m7G score was related to remarkable upregulation of the PD-1 and PD-L1, the higher TMB and the lower TIDE score.ConclusionThis study established a m7G-related signature for predicting prognosis and immunotherapy in LUAD, which may contribute to the development of new therapeutic strategies for LUAD.

Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. Disruption of tissue homeostasis often results in many diseases. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological and pathological conditions remains poorly understood. Here, we find that the evolutionarily conserved endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation and intestinal homeostasis. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, the EMC associates with and stabilizes Hippo (Hpo) protein, the key component of the Hpo signaling pathway. In the absence of EMC, Yorkie (Yki) is activated to promote ISC proliferation due to Hpo destruction. The EMC-Hpo-Yki axis also functions in enterocytes to maintain intestinal homeostasis. Importantly, the levels of the EMC are dramatically diminished in tunicamycin-treated animals, leading to Hpo destruction, thereby resulting in intestinal homeostasis disruption due to Yki activation. Thus, our study uncovers the molecular mechanism underlying the action of the EMC in intestinal homeostasis maintenance under physiological and pathological conditions and provides new insight into the pathogenesis of tunicamycin-induced tumorigenesis. [ABSTRACT FROM AUTHOR]

Pressurized electroslag remelting （PESR） is currently the most effective production route for industrial preparation of high nitrogen steel and high nitrogen alloys， and is currently a research focus and the most advanced technology in the field of electroslag metallurgy. This article introduces the development of the integrated line equipments， process technology， and main product characteristics of PESR. A review is conducted on the core components of the nitrogen alloy feeding system and water-gas dynamic balance system in the current PESR furnace equipment. In response to the current technological difficulties in PESR process， this paper elaborates on the development of new technologies such as the mechanism and method of nitrogen addition and gas-phase nitrogen addition technology for nitriding alloys， development of a new high-efficiency heating refining remelting slag system， and precise element control. In recent years， with the application of series newly built domestically produced pilot scale PESR furnaces and the successful development of series of high nitrogen steel products， China has made a significant breakthroughs in the integrated line equipment independent research and technological development， and gradually stepped forward to the international advanced level.At the same time， deepening the independent research and development of industrial grade PESR equipment and process technology research and development， ensuring the preparation of key materials urgently needed for high-quality special steels and special alloys in China's aviation， aerospace， and military industries fields and so on， is an important direction for the development of modern electroslag metallurgy technology in China.