Comprehensive analysis of the interaction of antigen presentation during anti-tumour immunity and establishment of AIDPS systems in ovarian cancer.

There are hundreds of prognostic models for ovarian cancer. These genes are based on different gene classes, and there are many ways to construct the models. Therefore, this paper aims to build the most stable prognostic evaluation system known to date through 101 machine learning strategies. We combined 101 algorithm combinations with 10 machine learning algorithms to create antigen presentation-associated genetic markers (AIDPS) with outstanding precision and steady performance. The inclusive set of algorithms comprises the elastic network (Enet), Ridge, stepwise Cox, Lasso, generalized enhanced regression model (GBM), random survival forest (RSF), supervised principal component (SuperPC), Cox partial least squares regression (plsRcox), survival support vector machine (Survival-SVM). Then, in the train cohort, the prediction model was fitted using a leave-one cross-validation (LOOCV) technique, which involved 101 different possible combinations of prognostic genes. Seven validation data sets (GSE26193, GSE26712, GSE30161, GSE63885, GSE9891, GSE140082 and ICGC_OV_AU) were compared and analysed, and the C-index was calculated. Finally, we collected 32 published ovarian cancer prognostic models (including mRNA and lncRNA). All data sets and prognostic models were subjected to a univariate Cox regression analysis, and the C-index was calculated to demonstrate that the antigen presentation process should be the core criterion for evaluating ovarian cancer prognosis. In a univariate Cox regression analysis, 22 prognostic genes were identified based on the expression profiles of 283 genes involved in antigen presentation and the intersection of genes (p < 0.05). AIDPS were developed by our machine learning-based integration method, which was applied to these 22 genes. One hundred and one prediction models are fitted using the LOOCV framework, and the C-index is calculated for each model across all validation sets. Interestingly, RSF + Lasso was the best model overall since it had the greatest average C-index and the highest C-index of any combination of models tested on the validated data sets. In comparing external cohorts, we found that the C-index correlated AIDPS method using the RSF + Lasso method in 101 prediction models was in contrast to other features. Notably, AIDPS outperformed the vast majority of models across all data sets. Antigen-presenting anti-tumour immune pathways can be used as a representative gene set of ovarian cancer to track the prognosis of patients with cancer. The antigen-presenting model obtained by the RSF + Lasso method has the best C-INDEX, which plays a key role in developing antigen-presenting targeted drugs in ovarian cancer and improving the treatment outcome of patients.

An immunogenic cell death-related classification predicts prognosis and response to immunotherapy in kidney renal clear cell carcinoma.

Introduction: Immunogenic cell death (ICD) is a form of regulated cell death that activates an adaptive immune response in an immunocompetent host and is particularly sensitive to antigens from tumor cells. Kidney clear cell carcinoma (KIRC) is an immunogenic tumor with extensive tumor heterogeneity. However, no reliable predictive biomarkers have been identified to reflect the immune microenvironment and therapeutic response of KIRC. Methods: Therefore, we used the CIBERSORT and ESTIMATE algorithms to define three ICD clusters based on the expression of ICD-related genes in 661 KIRC patients. Subsequently, we identified three different ICD gene clusters based on the overlap of differentially expressed genes (DEGs) within the ICD clusters. In addition, principal component analysis (PCA) was performed to calculate the ICD scores. Results: The results showed that patients with reduced ICD scores had a poorer prognosis and reduced transcript levels of immune checkpoint genes regulated with T cell differentiation. Furthermore, the ICD score was negatively correlated with the tumor mutation burden (TMB) value of KICD. patients with higher ICD scores showed clinical benefits and advantages of immunotherapy, indicating that the ICD score is an accurate and valid predictor to assess the effect of immunotherapy. Discussion: Overall, our study presents a comprehensive KICD immune-related ICD landscape that can provide guidance for current immunotherapy and predict patient prognosis to help physicians make judgments about the patient's disease and treatment modalities, and can guide current research on immunotherapy strategies for KICD.

Bibliometric analysis and mini-review of global research on pyroptosis in the field of cancer.

Pyroptosis is one of the mechanisms of programmed cell death (PCD) activated by inflammasomes and involved by the caspase family and the gasdermin family. During the oncogenesis and progression of tumors, pyroptosis is crucial, and complex withal. Currently, pyroptosis is the focus topic in the research field of oncology, but there is no single bibliometric analysis systematically studying 'pyroptosis and cancer'. Our study aimed to visualize the research status of pyroptosis in oncology and excavate the hotspots and prospects in this field. Furthermore, in consideration of the professional direction of researchers, we particularly emphasized articles on pyroptosis in gynecology and formed a mini systematic review. This bibliometric work integrated and analyzed all articles from ISI Web of Science: Science Citation Index Expanded (SCI-Expanded) (dated April 25th, 2022), based on quantitative and visual mapping approaches. Systematically reviewing articles on pyroptosis in gynecology helped us complement our analysis of research advancements in this field. Including 634 articles, our study found that the number of articles on pyroptosis in cancer increased exponentially in recent years. These publications came from 45 countries and regions headed by China and the US mainly aiming at the mechanism of pyroptosis in cell biology and biochemistry molecular biology, as well as the role of pyroptosis in the development and therapeutic application of various cancers. The top 20 most cited studies on this topic mostly came from the US, followed by China and England, and half of the articles cited more than 100 times in total were published in Nature. Moreover, as for gynecologic cancer, in vitro and bioinformatics analysis were the main methodology conducting to explore roles of pyroptosis-related genes (PRGs) and formation of inflammasomes in cancer progression and prognosis. Pyroptosis has evolved into a burgeoning research field in oncology. The cellular and molecular pathway mechanism of pyroptosis, as well as the effect of pyroptosis in oncogenesis, progression, and treatment have been the hot topic of the current study and provided us the future direction as the potential opportunities and challenges. We advocate more active cooperation to improve therapeutic strategies for cancer.

TEM1 up-regulates MMP-2 and promotes ECM remodeling for facilitating invasion and migration of uterine sarcoma.

OBJECTIVES: To explore the correlation between tumor endothelial marker 1 (TEM1) and matrix metalloproteinase 2 (MMP-2) in uterine sarcoma and their roles in the progression of uterine sarcoma. METHODS: Uterine leiomyosarcoma (uLMS, n = 25) and uterine leiomyoma (n = 25) specimens were collected from a total of 50 patients. Immunohistochemistry assay was conducted to determine the expression of TEM1, MMP-2 and MMP-9. TEM1 over expression (hTEM1) and low expression (shRNA-TEM1) MES-SA cell lines were established as in vitro uterine sarcoma models. MMP-2 mRNA, protein expression and enzymatic activity were verified using qPCR, Western blot and gelatin zymography respectively. MMP-2 expression was downregulated using MMP-2 siRNA in hTEM1 MES-SA cells to better study the role of MMP-2. The invasive and migratory capacities of hTEM1, shRNA-TEM1, and hTEM1 treated with MMP-2 siRNA MES-SA cells were determined using transwell assays. Extracellular matrix (ECM) remodeling mediated by TEM1 was examined using cell-ECM adhesion and fluorescent gelatin-ECM degradation assays. The immunofluorescence of F-actin was examined to analyze the formation of invadopodia. Subcutaneous and intraperitoneal xenografts were established to validate the role of TEM1 in promoting uterine sarcoma metastasis. RESULTS: TEM1 and MMP-2 were expressed in 92% (n = 23) and 88% (n = 22) of uterine leiomyosarcoma specimens, respectively. Both TEM1 and MMP-2 were highly expressed in 100% (n = 17) of high stage (III-IV) uterine leiomyosarcoma specimens. In addition, TEM1 expression was positively correlated with MMP-2 expression in uterine leiomyosarcoma. The successful establishment of in vitro uterine sarcoma models was confirmed with qPCR and Western blotting tests. TEM1 promoted the invasion and metastasis of uterine sarcoma in vivo and in vitro. MMP-2 expression and activity were up-regulated in hTEM1 cells but down-regulated in shRNA-TEM1 cells. Importantly, MMP-2 knockdown impaired the invasive and migratory capacity of hTEM1 cells. TEM1 promoted ECM remodeling by increasing cell-ECM adhesion and ECM degradation. TEM1 overexpression also induced the formation of invadopodia. CONCLUSION: TEM1 was co-expressed and positively correlated with MMP-2 in uterine leiomyosarcoma specimens. In addition, both TEM1 and MMP-2 were associated with tumor development. TEM1 promoted uterine sarcoma progression by regulating MMP-2 activity and ECM remodeling.

Alternative ANKHD1 transcript promotes proliferation and inhibits migration in uterine corpus endometrial carcinoma.

Alternative splicing (AS) is common in gene expression, and abnormal splicing often results in several cancers. Overall survival-associated splicing events (OS-SEs) have been used to predict prognosis in cancer. The aim of this study was to investigate the presence and function of OS-SEs in uterine corpus endometrial carcinoma (UCEC). Based on TCGA and TCGASpliceSeq databases, gene expression and the AS data of UCEC samples were retrieved. An alternate terminator of ANKHD1 transcripts named ANKHD1-BP3 was found to be significantly related to metastasis and OS in UCEC and significantly associated with HSPB1. The upregulated expression of HSPB1 induced downregulation of ANKHD1-BP3 and promoted tumor metastasis. These findings indicate that HSPB1, a splicing factor, regulates the expression of ANKHD1-BP3 to promote metastasis in UCEC.

Ral GEF with the PH Domain and SH3 Binding Motif 1 Regulated by Splicing Factor Junction Plakoglobin and Pyrimidine Metabolism Are Prognostic in Uterine Carcinosarcoma.

Uterine carcinosarcoma (UCS) is a highly invasive malignant tumor that originated from the uterine epithelium. Many studies suggested that the abnormal changes of alternative splicing (AS) of pre-mRNA are related to the occurrence and metastasis of the tumor. This study investigates the mechanism of alternative splicing events (ASEs) in the tumorigenesis and metastasis of UCS. RNA-seq of UCS samples and alternative splicing event (ASE) data of UCS samples were downloaded from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases, several times. Firstly, we performed the Cox regression analysis to identify the overall survival-related alternative splicing events (OSRASEs). Secondly, a multivariate model was applied to approach the prognostic values of the risk score. Afterwards, a coexpressed network between splicing factors (SFs) and OSRASEs was constructed. In order to explore the relationship between the potential prognostic signaling pathways and OSRASEs, we fabricated a network between these pathways and OSRASEs. Finally, validations from multidimension platforms were used to explain the results unambiguously. 1,040 OSRASEs were identified by Cox regression. Then, 6 OSRASEs were incorporated in a multivariable model by Lasso regression. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was 0.957. The risk score rendered from the multivariate model was corroborated to be an independent prognostic factor (P < 0.001). In the network of SFs and ASEs, junction plakoglobin (JUP) noteworthily regulated RALGPS1-87608-AT (P < 0.001, R = 0.455). Additionally, RALGPS1-87608-AT (P = 0.006) showed a prominent relationship with distant metastasis. KEGG pathways related to prognosis of UCS were selected by gene set variation analysis (GSVA). The pyrimidine metabolism (P < 0.001, R = -0.470) was the key pathway coexpressed with RALGPS1. We considered that aberrant JUP significantly regulated RALGPS1-87608-AT and the pyrimidine metabolism pathway might play a significant part in the metastasis and prognosis of UCS.

Identification of Stemness-Related Genes for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma by Integrated Bioinformatics Analysis.

BACKGROUND: Invasion and metastasis of cervical cancer are the main factors affecting the prognosis of patients with cervical squamous cell carcinoma (CESC). Therefore, it is of vital importance to find novel biomarkers that are associated with CESC invasion and metastasis, which will aid in the amelioration of individualized therapeutic methods for advanced patients. METHODS: The gene expression profiles of 10 metastatic and 116 non-metastatic samples were downloaded from The Cancer Genome Atlas (TCGA), where differentially expressed genes (DEGs) were defined. Weighted gene correlation network analysis (WGCNA) was employed to identify the stemness-related genes (SRGs). Univariate and multivariate regression analyses were used to identify the most significant prognostic key genes. Differential expression analysis of transcription factor (TF) and Gene Set Variation Analysis (GSVA) were utilized to explore the potential upstream regulation of TFs and downstream signaling pathways, respectively. Co-expression analysis was performed among significantly enriched TFs, key SRGs, and signaling pathways to construct a metastasis-specific regulation network in CESC. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for the network. Additionally, direct regulatory patterns of key genes were validated by ChIP-seq and ATAC-seq data. RESULTS: DEGs in yellow module acquired via WGCNA were defined as key genes which were most significantly related to mRNAsi. A multivariate Cox regression model was constructed and then utilized to explore the prognostic value of key SRGs by risk score. Area under curve (AUC) of the receiver operating characteristic (ROC) curve was 0.842. There was an obvious co expression pattern between the TF NR5A2 and the key gene VIM (R = 0.843, p < 0.001), while VIM was also significantly co-expressed with hallmark epithelial mesenchymal transition (EMT) signaling pathway (R = 0.318, p < 0.001). Naringenin was selected as the potential bioactive small molecule inhibitor for metastatic CESC based on CMap analysis. CONCLUSIONS: VIM positively regulated by NR5A2 affected EMT signaling pathways in metastatic CESC, and naringenin was the inhibitor for the treatment of metastatic CESC via suppressing cancer stemness. This hypothetical signaling axis and potential inhibitors provide biomarkers and novel therapeutic targets for metastatic CESC.

Co-expression Analysis of Genes and Tumor-Infiltrating Immune Cells in Metastatic Uterine Carcinosarcoma.

Uterine carcinosarcoma (UCS) is a malignant tumor with a high tendency to invasion and metastasis. However, the underlying invasion and metastasis mechanisms of UCS remain poorly understood. Genetic alteration and tumor-infiltrating immune cells play important roles in tumorigenesis, progression, and metastasis. To better understand the underlying mechanisms of UCS, we screened tumor-infiltrating immune cells by applying CIBERSORT algorithm and constructed nomograms to predict the prognosis of UCS patients based on metastasis-specific tumor-infiltrating immune cells and genes, and demonstrated their utility by the high AUC values. Combining gene co-expression and experimental validation results, we propose a potential mechanism of AK8, MPZ, and mast cells activated might play important parts in UCS metastasis.

Removal of colloidal precipitation plugging with high-power ultrasound.

Petroleum is a continuous and dynamically stable colloidal system. In the process of oil extraction, transportation, and post-treatment, the stability of the petroleum sol system is easily destroyed, resulting in asphaltenes precipitation that can make pore throat, oil wells, and pipelines blocked, thereby damaging the reservoir and reducing oil recovery. In this paper, removing near-well plugging caused by asphaltene deposition with high-power ultrasound is investigated. Six PZT transducers with different parameters were used to carry out the experimental study. Results show that ultrasonic frequency is one important factor for removing colloidal precipitation plugging in cores, it could not be too high nor too low. The optimum ultrasonic frequency is 25 kHz; Selecting transducers with a higher power is an effective way to improve the removal efficiency. The optimum ultrasonic power is 1000 W. With the increase of ultrasonic treatment time, the recovery rate reaches the maximum and tends to be stable. ultrasonic processing time should be controlled within 120 min. Besides, three methods - ultrasonic treatment alone, chemical injection alone, and ultrasound-chemical method - for removing colloidal precipitation plugging are compared. Results indicate that the ultrasound-assisted chemical method is better than chemical injection alone or ultrasonic treatment alone to remove colloidal sediment in the core. Finally, the mechanism of the ultrasonic deplugging technique is analyzed from three aspects: cavitation effect, the thermal effect, and mechanical vibration.

Effects of Tra2-beta1 on proliferation, apoptosis, and metastasis of hypoxic endometrial carcinoma cell and its correlation with clinicopathological features.

BACKGROUND: This study aims to examine the influence of human transformer-2-beta1 (Tra2-beta1) on endometrial carcinoma (EC) development. The effects of Tra2-beta1 on the proliferation, apoptosis, invasion, and cell cycle of EC cells were also investigated. METHODS: Functional in vitro experiments were performed on Tra2-beta1 knockdown cells and hypoxic model cells. Western blot was used to detect HIF-1a, vascular endothelial growth factor (VEGF), and Tra2-beta1 protein expression; CCK8 assay was used to detect cell proliferation; flow cytometry was used to detect apoptosis and cell cycle, and Transwell assay was used to detect cell invasion ability. Tumor specimens were collected from 128 consecutive patients to detect the expression of Tra2-beta1, and the relationship between and EC and Tra-beta1 were analyzed by clinical pathological data, which included lymph node metastasis, pathological types, histological grade, myometrial invasion, etc. RESULTS: Tra2-beta1 was highly expressed in EC and was associated with clinical pathological features. It was related to the prognosis, and was found to promote proliferation (F=48.3, P<0.001) and migration (P<0.05), and inhibit apoptosis (P<0.05). Statistical analyses revealed a positive correlation between Tra2-beta1 and HIF-1a (correlation coefficient =0.36, P<0.001) and VEGF protein (correlation coefficient =0.23, P=0.021). In the hypoxic cell group and the combined intervention group, cell proliferation after 72 h was 9,783±45.6 and 6,783±68.4 (P<0.001), while the number of invasive cells was 421±16.8 and 276±11.2 (P<0.001), respectively. The apoptosis rates were 0.45±0.03 and 1.28±0.16, respectively (P<0.05). CONCLUSIONS: The present findings demonstrate that the development of EC is positively correlated with Tra2-beta1. Tra2-beta1 may reverse the effect of hypoxia on EC, and this may provide new insights into the occurrence and development of EC.