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To tackle misdiagnosis in lung cancer screening with low-dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in - early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo-methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1-4) with distinct molecular features and immune cell infiltrations: EGFR-driven G1, EGFR/TP53 co-mutation G2, inflamed G3, stem-like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer.

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Introduction: The mechanism of thymoma-associated myasthenia gravis (TAMG) is currently unknown, although patients with TAMG experience more severe myasthenic symptoms and have worse prognoses compared to regular thymoma patients. The objective of this research is to create a transcriptome map of TAMG using genes linked to disulfidptosis, detect possible biomarkers, and examine the disparities in the tumor immune microenvironment (TIME) among different thymoma patients. The findings will offer valuable knowledge for personalized treatment alternatives. Methods: Thymoma samples' RNA-seq data, along with their corresponding clinical data, were acquired from the TCGA database using methods. Next, genes and disulfidptosis-related lncRNAs(DRLs) were chosen through correlation analysis. Then, a prediction model of TAMG was established by LASSO regression. Subsequent to that, an analysis of the mutation data, the tumor mutational burden (TMB), and the assessment of immune and stromal elements within the tumor microenvironment were conducted. Results: A total of 87 patients diagnosed with thymoma were included in the study, with 29 of them having TAMG. We discovered a group of 325 lncRNAs in this sample that showed significant associations with genes related to disulfidptosis, with 25 of them displaying significantly altered expression. Moreover, utilizing LASSO regression, we constructed a predictive model incorporating 11 DRLs. The analysis revealed an area under the curve (AUC) of 0.934 (CI 0.879-0.989), a cut-off value of 0.797, along with a sensitivity of 82.8 % and specificity of 93.1 %. Furthermore, we examined the TIME in both the high-risk and low-risk groups, and observed noteworthy disparities in B cells, T cells, and APC among the two groups (p < 0.05). Conclusion: This research offers the initial examination of genes associated with disulfidptosis and TAMG through genomic and transcriptomic analysis. Furthermore, a strong risk forecasting model was created and the significance of TIME in TAMG was also clarified. The discoveries offer significant understanding into the molecular processes of TAMG and present possible indicators for categorizing risk.

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BACKGROUND: Tumor-associated inflammation suggests that anti-inflammatory medication could be beneficial in cancer therapy. Loratadine, an antihistamine, has demonstrated improved survival in certain cancers. However, the anticancer mechanisms of loratadine in lung cancer remain unclear. OBJECTIVE: This study investigates the anticancer mechanisms of loratadine in lung cancer. METHODS: A retrospective cohort of 4,522 lung cancer patients from 2006 to 2018 was analyzed to identify noncancer drug exposures associated with prognosis. Cellular experiments, animal models, and RNA-seq data analysis were employed to validate the findings and explore the antitumor effects of loratadine. RESULTS: This retrospective study revealed a positive association between loratadine administration and ameliorated survival outcomes in lung cancer patients, exhibiting dose dependency. Rigorous in vitro and in vivo assays demonstrated that apoptosis induction and epithelial-mesenchymal transition (EMT) reduction were stimulated by moderate loratadine concentrations, whereas pyroptosis was triggered by elevated dosages. Intriguingly, loratadine was found to augment PPARγ levels, which acted as a gasdermin D transcription promoter and caspase-8 activation enhancer. Consequently, loratadine might incite a sophisticated interplay between apoptosis and pyroptosis, facilitated by the pivotal role of caspase-8. CONCLUSION: Loratadine use is linked to enhanced survival in lung cancer patients, potentially due to its role in modulating the interplay between apoptosis and pyroptosis via caspase-8.

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Using Mendelian Randomization (MR) and large-scale Genome-Wide Association Study (GWAS) data, this study aimed to investigate the potential causative relationship between testosterone and sex hormone-binding globulin (SHBG) levels and the onset of several cancers, including pathway enrichment analyses of single nucleotide polymorphisms (SNPs) associated with cancer allowed for a comprehensive bioinformatics approach, which offered a deeper biological understanding of these relationships. The results indicated that increased testosterone levels in women were associated with a higher risk of breast and cervical cancers but a lower risk of ovarian cancer. Conversely, increased testosterone was linked to lower stomach cancer risk for men, whereas high SHBG levels were related to decreased risks of breast and prostate cancers. The corresponding genes of the identified SNPs, as revealed by pathway enrichment analysis, were involved in significant metabolic and proliferative pathways. These findings emphasize the need for further research into the biological mechanisms behind these associations, paving the way for potential targeted interventions in preventing and treating these cancers.

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Cellular senescence contributes to cancer pathogenesis and immune regulation. Using the LASSO Cox regression, we developed a 12-gene prognostic signature for lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) and a Gene Expression Omnibus (GEO) dataset. We assessed gene expression, drug sensitivity, immune infiltration, and conducted cell line experiments. High-risk LUAD patients showed increased mortality risk and shorter survival (P < 0.001). Senescence-related gene analysis indicated differences in protein phosphorylation and DNA methylation between normal individuals and LUAD patients. The high-risk group showed a positive association with PD-L1 expression (P = 0.003). Single-cell sequencing data suggested PEBP1 might significantly impact T cell infiltration. We predicted potential sensitive compounds for 12 senescence genes and found GAPDH promoted cell line proliferation. We established a novel prognostic system based on a newly identified senescence gene. High-risk patients had elevated immunosuppressive markers, and PEBP1 might influence T cell infiltration significantly. GAPDH, expressed at higher levels in tumors, could affect cancer progression. Our drug prediction model may guide treatment selection.

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The intracellular application of DNA nanodevices is challenged by their inadequate cellular entry efficiency, which may be addressed by the development of amphiphilic DNA nanostructures. However, the impact of the spatial distribution of hydrophobicity in cell entry has not been fully explored. Here, we program a spectrum of amphiphilic DNA nanostructures displaying diverse sub-10 nm patterns of cholesterol, which result in distinct aggregate states in the aqueous solution and thus varied cell entry efficiencies. We find that the hydrophobic patterns can lead to discrete aggregate states, from monomers to low-number oligomers (n = 1-6). We demonstrate that the monomers or oligomers with moderate hydrophobic density are preferred for cell entry, with up to ∼174-fold improvement relative to unmodified ones. Our study provides a new clue for the rational design of amphiphilic DNA nanostructures for intracellular applications.

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Background: Respiratory cancer is the leading cause of cancer-related deaths worldwide, but its statistics vary between the East and West. This study aimed to estimate the burdens of tracheal, bronchus, and lung (TBL) cancer and larynx cancer and their attributable risks from 1990 to 2019 in Asia, and at regional and national levels. Methods: This research evaluated the incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) for respiratory tract cancers using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 database. Age-standardized rates were calculated for TBL cancer from 1990 to 2019, adjusted for smoking and socio-demographic index (SDI). Deaths from TBL cancer and larynx cancer attributable to each risk factor were estimated for 33 Asian countries. Results: The age-standardized incidence and death rates for TBL cancer in Asia declined from 2010 to 2019, while the incidence rate of larynx cancer increased. Smoking was the leading specific risk factor for deaths from both TBL and larynx cancers. The burden of TBL cancer in Asian countries was influenced by SDI and smoking, particularly among males in Central Asia. Deaths, DALYs, and incidences of larynx cancer in East Asia had not changed significantly over the past 30 years, but showed slight downward trends in males and both sexes combined, and an upward trend in females in recent years. Conclusions: The past decade saw increases in numbers of incident cases and deaths from TBL cancer and larynx cancer in Asia. SDI and smoking were the main factors influencing the disease burden of TBL cancer in Asian countries. This study highlights the need for tailored cancer control programs to address the burden of respiratory tract cancers in different Asian countries.

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Background: The efficiency of immune checkpoint inhibitors (ICIs) in bladder cancer (BLCA) treatment has been widely validated; however, the tumor response to ICIs was generally low. It is critical and urgent to find biomarkers that can predict tumor response to ICIs. The tumor microenvironment (TME), which may play important roles to either dampen or enhance immune responses, has been widely concerned. Methods: The cancer genome atlas BLCA (TCGA-BLCA) cohort (n = 400) was used in this study. Based on the proportions of 22 types of immune cells calculated by CIBERSORT, TME was classified by K-means Clustering and differentially expressed genes (DEGs) were determined. Based on DEGs, patients were classified into three groups, and cluster signature genes were identified after reducing redundant genes. Then TMEscore was calculated based on cluster signature genes, and the samples were classified to two subtypes. We performed somatic mutation and copy number variation analysis to identify the genetic characteristics of the two subtypes. Correlation analysis was performed to explore the correlation between TMEscore and the tumor response to ICIs as well as the prognosis of BLCA. Results: According to the proportions of immune cells, two TME clusters were determined, and 1,144 DEGs and 138 cluster signature genes were identified. Based on cluster signature genes, samples were classified into TMEscore-high (n = 199) and TMEscore-low (n = 201) subtypes. Survival analysis showed patients with TMEscore-high phenotype had better prognosis. Among the 45 differentially expressed micro-RNAs (miRNAs) and 1,033 differentially expressed messenger RNAs (mRNAs) between the two subtypes, 16 miRNAs and 287 mRNAs had statistically significant impact on the prognosis of BLCA. Furthermore, there were 94 genes with significant differences between the two subtypes, and they were enriched in RTK-RAS, NOTCH, WNT, Hippo, and PI3K pathways. The Tumor Immune Dysfunction and Exclusion (TIDE) score of TMEscore-high BLCA was statistically lower than that of TMEscore-low BLCA. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of TMEscore and tumor mutation burden (TMB) is 0.6918 and 0.5374, respectively. Conclusion: We developed a method to classify BLCA patients to two TME subtypes, TMEscore-high and TMEscore-low, and we found TMEscore-high subtype of BLCA had a good prognosis and a good response to ICIs.

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OBJECTIVE: Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers, but its pathogenesis has not been fully elucidated. Therefore, it is valuable to explore the pathogenesis of NSCLC to improve diagnosis and identify novel treatment biomarkers. METHODS: Circular (circ)RNA, micro (mi)RNA, and gene expression datasets of NSCLC were analyzed to identify those that were differentially expressed between tumor and healthy tissues. Common genes were found and pathway enrichment analyses were performed. Survival analysis was used to identify hub genes, and their level of methylation and association with immune cell infiltration were analyzed. Finally, an NSCLC circRNA-miRNA-mRNA network was constructed. RESULTS: Eight miRNAs and 211 common genes were identified. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that cell projection morphogenesis, blood vessel morphogenesis, muscle cell proliferation, and synapse organization were enriched. Ten hub genes were found, of which the expression of DTL and RRM2 was significantly related to NSCLC patient prognosis. Significant methylation changes and immune cell infiltration correlations with DTL and RRM2 were also detected. CONCLUSIONS: hsa_circ_0001947/hsa-miR-637/RRM2 and hsa_circ_0072305/hsa-miR-127-5p/DTL networks were constructed, and identified molecules may be involved in the occurrence and development of NSCLC.

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