Abstract Background Disulfidptosis is a new type of regulated cell death that involves cytoskeletal collapse, induced by excessive disulfide bond formation. However, understanding of the biological characteristics and clinical significance of disulfidptosis in pan-cancers remains limited. Methods We obtained transcriptome data from TCGA via UCSC Xena. Based on the expression of disulfidptosis-related genes (DRG), we constructed a consensus DRG-related signature (DRGS) using the LASSO Cox regression model. A nomogram incorporating the DRG score was developed as a quantitative tool for predicting prognosis. We utilized the z-score algorithm to integrate gene expression characteristics and activity of specific pathways. Comprehensive analyses were performed to investigate tumor microenvironment and mutation profiles. We evaluated the responses of subgroups to immunotherapy and conducted drug screening. Finally, we utilized immunofluorescence (IF) to evaluate the expression of hub genes in patients with ovarian cancer (OV). Results The DRGS was considered a prognostic factor for various types of cancer, with higher scores indicating more unfavorable outcomes. DRGS can also serve as a predictive indicator for various malignant biological processes. The independent prognostic significance for survival was confirmed using multivariate analysis. The group characterized by high expression levels of inverted formin 2 (INF2) demonstrated an attenuated response to palbociclib treatment and an immunosuppressive phenotype. In OV, INF2 was associated with poor clinical outcomes. Conclusion Our study demonstrated a prognostic DRGS, which holds great promise as a robust tool for uncovering clinical characteristics, predicting survival outcomes, and reflecting the response to targeted therapy across various cancer types.
Abstract KIAA1429 is an important ‘writer’ of the N6‐methyladenine (m 6 A) modification, which is involved in tumour progression. This study was conducted to explore the mechanism of action of KIAA1429 in colon adenocarcinoma (COAD). KIAA1429 ‐silenced COAD cell and xenograft tumour models were constructed, and the function of KIAA1429 was explored through a series of in vivo and in vitro assays. The downstream mechanisms of KIAA1429 were explored using transcriptome sequencing. Dimethyloxalylglycine (DMOG), an activator of HIF‐1α , was used for feedback verification. The expression of KIAA1429 in COAD tumour tissues and cells was elevated, and KIAA1429 exhibited differential expression at different stages of the tumour. Silencing of KIAA1429 inhibited the proliferation, migration, and invasion of HT29 and HCT116 cells. The expression levels of NLRP3 , GSDMD and Caspase‐1 were decreased in KIAA1429 ‐silenced HT29 cells, indicating the pyroptotic activity was inhibited. Additionally, KIAA1429 silencing inhibited the growth of tumour xenograft. Transcriptome sequencing and reverse transcription quantitative polymerase chain reaction revealed that after KIAA1429 silencing, the expression of AKR1C1 , AKR1C2 , AKR1C3 and RDH8 was elevated, and the expression of VIRMA , GINS1 , VBP1 and ARF3 was decreased. In HT29 cells, KIAA1429 silencing blocked the HIF‐1 signalling pathway, accompanied by the decrease in AKT1 and HIF‐1α protein levels. The activation of HIF‐1 signalling pathway, mediated by DMOG, reversed the antitumour role of KIAA1429 silencing. KIAA1429 silencing inhibits COAD development by blocking the HIF‐1 signalling pathway.
In recent years, immunotherapy has been emerging as a promising alternative therapeutic method for cancer patients, offering potential benefits. The expression of PD-L1 by tumors can inhibit the T-cell response to the tumor and allow the tumor to evade immune surveillance. To address this issue, cancer immunotherapy has shown promise in disrupting the interaction between PD-L1 and its ligand PD-1.
Colon adenocarcinoma (COAD) is a frequent malignancy of the digestive system with a poor prognosis and high mortality rate worldwide. Intratumor heterogeneity (ITH) is associated with tumor progression, poor prognosis, immunosuppression, and therapy resistance. However, the relationship between ITH and prognosis, the immune microenvironment, and the chemotherapy response in COAD patients remains unknown, and this knowledge is urgently needed.We obtained clinical information and gene expression data for COAD patients from The Cancer Genome Atlas (TCGA) database. The DEPTH2 algorithm was utilized to evaluate the ITH score. X-tile software was used to determine the optimal cutoff value of the ITH score. The COAD patients were divided into high- and low-ITH groups based on the cutoff value. We analyzed prognosis, tumor mutation burden (TMB), gene mutations, and immune checkpoint expression between the high- and low-ITH groups. Differentially expressed genes (DEGs) in the high- and low-ITH groups were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. We performed univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses to screen the prognosis-related genes for the construction of an ITH-related prognostic signature. The nomogram was used to predict the overall survival (OS) of COAD patients. The protein-protein interaction (PPI) network was constructed by using the GeneMANIA database. Principal component analysis (PCA) and single-sample gene set enrichment analysis (ssGSEA) were employed to explore the differences in biological pathway activation status between the high- and low-risk groups. The proportion and type of tumor-infiltrating immune cells were evaluated by the CIBERSORT and ESTIMATE algorithms. Additionally, we assessed the chemotherapy response and predicted small-molecule drugs for treatment. Finally, the expression of the prognosis-related genes was validated by using the UALCAN database and Human Protein Atlas (HPA) database.The OS of the high-ITH group was worse than that of the low-ITH group. A positive correlation between ITH and TMB was identified. In subgroups stratified by age, gender, and tumor stage, the OS of the low-ITH group remained better than that of the high-ITH group. There were dramatic differences in the mutated genes, single nucleotide variant classes, variant types, immune checkpoints and cooccurring and mutually exclusive mutations of the DEGs between the high- and low-ITH groups. Based on the DEGs between the high- and low-ITH groups, we constructed a five-gene signature consisting of CEACAM5, ENO2, GABBR1, MC1R, and SLC44A4. The COAD patients were divided into high- and low-risk groups according to the median risk score. The OS of the high-risk group was worse than that of the low-risk group. The nomogram was used to accurately predict the 1-, 3- and 5-year OS of COAD patients and showed good calibration and moderate discrimination ability. The stromal score, immune score, and ESTIMATE score of the high-risk group were significantly higher than those of the low-risk group, whereas tumor purity showed the opposite trend. The patients classified by the risk score had distinguishable sensitivity to chemotherapeutic drugs. Finally, two public databases confirmed that CEACAM5 and SLC44A4 were upregulated in normal tissues compared with COAD tissues, and ENO2, GABBR1, and MC1R were upregulated in COAD tissues compared with normal tissues.Overall, we identified an ITH-related prognostic signature for COAD that was closely related to the tumor microenvironment and chemotherapy response. This signature may help clinicians make more personalized and precise treatment decisions for COAD patients.
The molecular history of animal evolution from single-celled ancestors remains a major question in biology, and little is known regarding the evolution of cell cycle regulation during animal emergence. In this study, we conducted a comprehensive evolutionary analysis of CDK and cyclin proteins in metazoans and their unicellular relatives. Our analysis divided the CDK family into eight subfamilies. Seven subfamilies (CDK1/2/3, CDK5, CDK7, CDK 20, CDK8/19, CDK9, and CDK10/11) are conserved in metazoans and fungi, with the remaining subfamily, CDK4/6, found only in eumetazoans. With respect to cyclins, cyclin C, H, L, Y subfamilies, and cyclin K and T as a whole subfamily, are generally conserved in animal, fungi, and amoeba Dictyostelium discoideum. In contrast, cyclin subfamilies B, A, E, and D, which are cell cycle-related, have distinct evolutionary histories. The cyclin B subfamily is generally conserved in D. discoideum, fungi, and animals, whereas cyclin A and E subfamilies are both present in animals and their unicellular relatives such as choanoflagellate Monosiga brevicollis and filasterean Capsaspora owczarzaki, but are absent in fungi and D. discoideum. Although absent in fungi and D. discoideum, cyclin D subfamily orthologs can be found in the early-emerging, non-opisthokont apusozoan Thecamonas trahens. Within opisthokonta, the cyclin D subfamily is conserved only in eumetazoans, and is absent in fungi, choanoflagellates, and the basal metazoan Amphimedon queenslandica. Our data indicate that the CDK4/6 subfamily and eumetazoans emerged simultaneously, with the evolutionary conservation of the cyclin D subfamily also tightly linked with eumetazoan appearance. Establishment of the CDK4/6-cyclin D complex may have been the key step in the evolution of cell cycle control during eumetazoan emergence.
Colon adenocarcinoma (COAD) is one of the most common clinically malignant tumours of the digestive system, with high incidence and mortality and poor prognosis. Interferon-gamma (IFN-γ) and long noncoding RNAs (lncRNAs) have prognostic values and were closely associated with immune microenvironment in COAD. Thus, identifying IFN-γ-related lncRNAs may be valuable in predicting the survival of patients with COAD. In this study, we identified IFN-γ-related lncRNAs and divided COAD patients from the Cancer Genome Atlas (TCGA) database into training and validation sets. Pearson’s correlation analysis and least absolute shrinkage and selection operator (LASSO) Cox regression were performed to select IFN-γ-related lncRNA-associated prognoses. Thirteen lncRNAs (AC025165.8, AC091633.3, FENDRR, LINC00882, LINC01828, LINC01829, MYOSLID, RP11-154H23.4, RP11-20J15.3, RP11-324L17.1, RP11-342A23.2, RP11-805I24.3, SERTAD4-AS1) were identified to construct an IFN-γ-related lncRNA prognostic signature in TCGA training (n =213) and validation (n =213) cohorts. COAD patient risk scores were calculated and classified into high- and low-risk groups based on the median value of the risk scores in each dataset. We compared the overall survival (OS) of patients stratified by age, gender, and stage. The OS in the high-risk group was significantly shorter than that in the low-risk group. In addition, the clinical nomogram incorporating the prognostic signature and clinical features showed a high concordance index of 0.78 and accurately predicted 1-, 3-, and 5-year survival times among COAD patients in the high- and low-risk groups. Based on the risk model, the high- and low-risk groups exhibited distinct differences in the immune system by gene set enrichment analysis (GSEA) functional annotation, and differentially expressed genes (DEGs) between the high- and low-risk groups were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We investigated the expression of multiple immune checkpoint genes in the high- and low-risk groups and plotted Kaplan-Meier survival curves, indicating that immune checkpoint genes, such as LAG3 and PD. L1, STING and TIM 3, were also expressed differently between the two risk groups. Subsequently, there were dramatic differences in mutated genes, SNV (single nucleotide variants) classes, variant types and variant allele frequencies between low- and high-risk patients with COAD. Patients stratified by risk scores had different sensitivities to common chemotherapeutic agents. Finally, we used quantitative real-time polymerase chain reaction (qRT-PCR) assays to demonstrate that three lncRNAs were significantly differentially expressed in COAD tissues and adjacent normal tissues. Considered together, a thirteen-lncRNA prognostic signature has great potential to be a prognostic biomarker and could play an essential role in the immune microenvironment of COAD.
Nutritional indicators have been implicated in the survival outcomes of various malignant tumors. However, there are few studies on the association between nutritional indicators and immunotherapy for esophageal cancer. The present study aimed to explore the value of nutritional indicators with regard to the survival outcomes in patients with metastatic esophageal squamous cell carcinoma (ESCC) treated with camrelizumab. A retrospective cohort analysis of 158 metastatic ESCC patients treated with camrelizumab in The Affiliated Xinghua People's Hospital, Medical School of Yangzhou University (Xinghua, China) between September 2019 and July 2022 was conducted. A receiver operating characteristic curve was used to determine the optimal cut-off values of prognostic nutritional index (PNI) and albumin (ALB). The cut-off value for body mass index (BMI) was set at the normal lower limit (18.5 kg/m2). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method, and the differences in PFS or OS between groups were compared using the log-rank test. The prognostic value of each variable was analyzed based on the univariate and multivariate Cox proportional hazards regression models. The optimal cutoff values of PNI, ALB and BMI were 41.35, 36.8 g/l and 18.5 kg/m2, respectively. Lower PNI, ALB and BMI were closely associated with shorter PFS [hazard ratio (HR) for PNI, 3.599; P<0.001; HR for ALB, 4.148; P<0.001; HR for BMI, 5.623; P<0.001) and OS (HR for PNI, 7.605; P<0.001; HR for ALB, 7.852; P<0.001; HR for BMI, 7.915; P<0.001) times. Univariate and multivariate Cox regression analyses indicated that lower PNI, ALB and BMI were independent risk factors of PFS and OS in patients with metastatic ESCC receiving camrelizumab treatment. In conclusion, PNI, ALB and BMI are promising predictive indicators to assess the survival outcomes in patients with metastatic ESCC treated with camrelizumab. Moreover, PNI, ALB and BMI may have prognostic significance in these patients.
Background: A tertiary lymphoid structure (TLS) is a crucial component of the tumor microenvironment (TME), which reflects the anti-tumor immune response in the host. This aim of the present study was to carry out a histopathological evaluation for TLS and assess its prognostic value in gastric cancer (GC). Methods: A total of 1,033 cases that has received a gastrectomy were reviewed, including 914 in the primary cohort and 119 in the validation cohort. TLS was assessed by optical microscopy and verified by immunohistochemistry. A total of 5 histopathological evaluation methods were compared in the primary cohort and validated in the validation cohort. In addition, MECA-79 and CD21 were used to verify the accuracy of the histopathological scoring system for TLS. The association among TLS, clinicopathological parameters and patient prognosis was analyzed. Results: TLS assessed by morphology and immunohistochemistry were significantly correlated and consistent. The morphological evaluation of TLS was accurate. Typically, the high level of TLS was significantly correlated with tumor size (P=0.047), histological grade (P=0.039), pTN stage (P=0.044), and WHO subtype (P<0.001). In addition, TLShi was a positive indicator of overall survival (OS), as determined by Kaplan-Meier survival (P=0.038) and multivariate Cox regression analysis (HR=0.794, 95% CI: 0.668-0.942, P=0.008). According to the results, TLShi had a positive effect on primary cohort patients with pTN stage II and III (P=0.027, P=0.042). Conclusions: The histopathological evaluation of TLS was accurate. Diagnosis based solely on Hematoxylin and Eosin staining of sections did not easily distinguish tumor-associated TLS. The density of TLS in the center of the tumor was found to be more indicative of patient prognosis than TLS in the invasive margin, with levels of total TLS shown to best correlate with overall survival in patients with advanced-stage GC.
Rapid on-site evaluation (ROSE) plays an important role during transbronchial sampling, providing an intraoperative cytopathologic evaluation. However, the shortage of cytopathologists limits its wide application. This study aims to develop a deep learning model to automatically analyze ROSE cytological images.
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