Genetic prediction of the relationship between metabolic syndrome and colorectal cancer risk: a Mendelian randomization study.

BACKGROUND: Despite a growing body of observational studies indicating a potential link between metabolic syndrome and colorectal cancer, a definitive causal relationship has yet to be established. This study aimed to elucidate the causal relationship between metabolic syndrome and colorectal cancer through Mendelian randomization. METHODS: We screened for instrumental variables associated with metabolic syndrome and its diagnostic components and with colorectal cancer through the use of a genome-wide association study database, and conducted a preliminary Mendelian randomization analysis. To corroborate the dependability of our conclusions, an additional dataset was used for replication analysis in a Mendelian randomization method, which was further integrated with a meta-analysis. RESULTS: Preliminary analysis using the inverse variance weighted method revealed positive correlations between metabolic syndrome (OR [95% CI] = 1.37[1.15-1.63], P = 5.02 × 10-4) and waist circumference (OR [95% CI] = 1.39[1.21-1.61], P = 7.38 × 10-6) and the risk of colorectal cancer. Replication analysis also revealed the same results: metabolic syndrome (OR [95% CI] = 1.24[1.02-1.51], P = 0.030) and waist circumference (OR [95% CI] = 1.23[1.05-1.45], P = 0.013). The meta-analysis results further confirmed the associations between metabolic syndrome (OR [95% CI] = 1.31[1.15-1.49], P < 0.001) and waist circumference (OR [95% CI] = 1.32[1.18-1.47], P < 0.001) and colorectal cancer. CONCLUSION: Our study indicated that metabolic syndrome increases the risk of CRC, particularly in patients with abdominal obesity.

Global trends in indocyanine green fluorescence navigation in the field of gastric cancer: bibliometrics and knowledge atlas analysis.

Background: Indocyanine green (ICG) fluorescence navigation can enhance the visualization of gastric cancer (GC) lesions, increase the lymph node detection rate, and reduce the incidence of anastomotic leakage in the treatment of GC. It thus holds considerable potential for application in GC clinical surgery and has attracted widespread research interest. The purpose of this study was to visualize the current topics and emerging trends in research regarding ICG in GC. Methods: We searched the Web of Science Core Collection (WoSCC) for articles relevant to the use of ICG in GC. The resulting information was then analyzed from a bibliometric and knowledge graph analysis perspective using CiteSpace, Scimago Graphica, and R Studio so that the key trends and hot spots in research within this field could be identified and visualized. Results: Ultimately, 1,385 papers from 58 countries or regions published from 1991 to 2022 were included in this study. The largest number of publications were from China, followed by Japan and the United States. High-yield institutions were concentrated in Asian countries, especially China. The top publication contributors were Shanghai Jiao Tong University. Li Y and Bang YJ ranked first among the top 10 most productive authors and top 10 most cocited authors, respectively. World Journal of Gastroenterology was the most productive academic journal on ICG in GC, while Cancer Research was the most commonly cocited journal. The keyword "indocyanine green" was among the top 5 keywords, and will likely remain a popular topic in future research. Furthermore, the emerging themes including surgery, biopsy, lymphadenectomy, dissection, and gastrectomy have attracted increasing attention. Conclusions: Current research hotspots in this area focus on the clinical implementation of ICG in precision surgery for GC. Given the imaging tracer characteristics of ICG and its utility in GC surgery, the optimization and application of ICG-guided precision surgery techniques for GC will be a research hot spot going forward.

Hub gene identification and molecular subtype construction for Helicobacter pylori in gastric cancer via machine learning methods and NMF algorithm.

Helicobacter pylori (HP) is a gram-negative and spiral-shaped bacterium colonizing the human stomach and has been recognized as the risk factor of gastritis, peptic ulcer disease, and gastric cancer (GC). Moreover, it was recently identified as a class I carcinogen, which affects the occurrence and progression of GC via inducing various oncogenic pathways. Therefore, identifying the HP-related key genes is crucial for understanding the oncogenic mechanisms and improving the outcomes of GC patients. We retrieved the list of HP-related gene sets from the Molecular Signatures Database. Based on the HP-related genes, unsupervised non-negative matrix factorization (NMF) clustering method was conducted to stratify TCGA-STAD, GSE15459, GSE84433 samples into two clusters with distinct clinical outcomes and immune infiltration characterization. Subsequently, two machine learning (ML) strategies, including support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF), were employed to determine twelve hub HP-related genes. Beyond that, receiver operating characteristic and Kaplan-Meier curves further confirmed the diagnostic value and prognostic significance of hub genes. Finally, expression of HP-related hub genes was tested by qRT-PCR array and immunohistochemical images. Additionally, functional pathway enrichment analysis indicated that these hub genes were implicated in the genesis and progression of GC by activating or inhibiting the classical cancer-associated pathways, such as epithelial-mesenchymal transition, cell cycle, apoptosis, RAS/MAPK, etc. In the present study, we constructed a novel HP-related tumor classification in different datasets, and screened out twelve hub genes via performing the ML algorithms, which may contribute to the molecular diagnosis and personalized therapy of GC.

Development and validation of a CT radiomics and clinical feature model to predict omental metastases for locally advanced gastric cancer.

""We employed radiomics and clinical features to develop and validate a preoperative prediction model to estimate the omental metastases status of locally advanced gastric cancer (LAGC). A total of 460 patients (training cohort, n = 250; test cohort, n = 106; validation cohort, n = 104) with LAGC who were confirmed T3/T4 stage by postoperative pathology were continuously collected retrospectively, including clinical data and preoperative arterial phase computed tomography images (APCT). Dedicated radiomics prototype software was used to segment the lesions and extract features from the preoperative APCT images. The least absolute shrinkage and selection operator (LASSO) regression was used to select the extracted radiomics features, and a radiomics score model was constructed. Finally, a prediction model of omental metastases status and a nomogram were constructed combining the radiomics scores and selected clinical features. An area under the curve (AUC) of the receiver operating characteristic curve (ROC) was used to validate the capability of the prediction model and nomogram in the training cohort. Calibration curves and decision curve analysis (DCA) were used to evaluate the prediction model and nomogram. The prediction model was internally validated by the test cohort. In addition, 104 patients from another hospital's clinical and imaging data were gathered for external validation. In the training cohort, the combined prediction (CP) model (AUC 0.871, 95% CI 0.798-0.945) of the radiomics scores combined with the clinical features, compared with clinical features prediction (CFP) model (AUC 0.795, 95% CI 0.710-0.879) and radiomics scores prediction (RSP) model (AUC 0.805, 95% CI 0.730-0.879), had the better predictive ability. The Hosmer-Lemeshow test of the CP model showed that the prediction model did not deviate from the perfect fitting (p = 0.893). In the DCA, the clinical net benefit of the CP model was higher than that of the CFP model and RSP model. In the test and validation cohorts, the AUC values of the CP model were 0.836 (95% CI 0.726-0.945) and 0.779 (95% CI 0.634-0.923), respectively. The preoperative APCT-based clinical-radiomics nomogram showed good performance in predicting omental metastases status in LAGC, which may contribute to clinical decision-making.

A bibliometric and visual analysis of publications on artificial intelligence in colorectal cancer (2002-2022).

Background: Colorectal cancer (CRC) has the third-highest incidence and second-highest mortality rate of all cancers worldwide. Early diagnosis and screening of CRC have been the focus of research in this field. With the continuous development of artificial intelligence (AI) technology, AI has advantages in many aspects of CRC, such as adenoma screening, genetic testing, and prediction of tumor metastasis. Objective: This study uses bibliometrics to analyze research in AI in CRC, summarize the field's history and current status of research, and predict future research directions. Method: We searched the SCIE database for all literature on CRC and AI. The documents span the period 2002-2022. we used bibliometrics to analyze the data of these papers, such as authors, countries, institutions, and references. Co-authorship, co-citation, and co-occurrence analysis were the main methods of analysis. Citespace, VOSviewer, and SCImago Graphica were used to visualize the results. Result: This study selected 1,531 articles on AI in CRC. China has published a maximum number of 580 such articles in this field. The U.S. had the most quality publications, boasting an average citation per article of 46.13. Mori Y and Ding K were the two authors with the highest number of articles. Scientific Reports, Cancers, and Frontiers in Oncology are this field's most widely published journals. Institutions from China occupy the top 9 positions among the most published institutions. We found that research on AI in this field mainly focuses on colonoscopy-assisted diagnosis, imaging histology, and pathology examination. Conclusion: AI in CRC is currently in the development stage with good prospects. AI is currently widely used in colonoscopy, imageomics, and pathology. However, the scope of AI applications is still limited, and there is a lack of inter-institutional collaboration. The pervasiveness of AI technology is the main direction of future housing development in this field.

Multiomics characteristics and immunotherapeutic potential of EZH2 in pan-cancer.

Enhancer of zeste homolog 2 (EZH2) is a significant epigenetic regulator that plays a critical role in the development and progression of cancer. However, the multiomics features and immunological effects of EZH2 in pan-cancer remain unclear. Transcriptome and clinical raw data of pan-cancer samples were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and subsequent data analyses were conducted by using R software (version 4.1.0). Furthermore, numerous bioinformatics analysis databases also reapplied to comprehensively explore and elucidate the oncogenic mechanism and therapeutic potential of EZH2 from pan-cancer insight. Finally, quantitative reverse transcription polymerase chain reaction and immunohistochemical assays were performed to verify the differential expression of EZH2 gene in various cancers at the mRNA and protein levels. EZH2 was widely expressed in multiple normal and tumor tissues, predominantly located in the nucleoplasm. Compared with matched normal tissues, EZH2 was aberrantly expressed in most cancers either at the mRNA or protein level, which might be caused by genetic mutations, DNA methylation, and protein phosphorylation. Additionally, EZH2 expression was correlated with clinical prognosis, and its up-regulation usually indicated poor survival outcomes in cancer patients. Subsequent analysis revealed that EZH2 could promote tumor immune evasion through T-cell dysfunction and T-cell exclusion. Furthermore, expression of EZH2 exhibited a strong correlation with several immunotherapy-associated responses (i.e., immune checkpoint molecules, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) status, and neoantigens), suggesting that EZH2 appeared to be a novel target for evaluating the therapeutic efficacy of immunotherapy.

Antisense-oligonucleotide-mediated perturbation of long non-coding RNA reveals functional features in stem cells and across cell types.

Within the scope of the FANTOM6 consortium, we perform a large-scale knockdown of 200 long non-coding RNAs (lncRNAs) in human induced pluripotent stem cells (iPSCs) and systematically characterize their roles in self-renewal and pluripotency. We find 36 lncRNAs (18%) exhibiting cell growth inhibition. From the knockdown of 123 lncRNAs with transcriptome profiling, 36 lncRNAs (29.3%) show molecular phenotypes. Integrating the molecular phenotypes with chromatin-interaction assays further reveals cis- and trans-interacting partners as potential primary targets. Additionally, cell-type enrichment analysis identifies lncRNAs associated with pluripotency, while the knockdown of LINC02595, CATG00000090305.1, and RP11-148B6.2 modulates colony formation of iPSCs. We compare our results with previously published fibroblasts phenotyping data and find that 2.9% of the lncRNAs exhibit a consistent cell growth phenotype, whereas we observe 58.3% agreement in molecular phenotypes. This highlights that molecular phenotyping is more comprehensive in revealing affected pathways.

Deep learning model for diagnosing early gastric cancer using preoperative computed tomography images.

Background: Early gastric cancer (EGC) is defined as a lesion restricted to the mucosa or submucosa, independent of size or evidence of regional lymph node metastases. Although computed tomography (CT) is the main technique for determining the stage of gastric cancer (GC), the accuracy of CT for determining tumor invasion of EGC was still unsatisfactory by radiologists. In this research, we attempted to construct an AI model to discriminate EGC in portal venous phase CT images. Methods: We retrospectively collected 658 GC patients from the first affiliated hospital of Nanchang university, and divided them into training and internal validation cohorts with a ratio of 8:2. As the external validation cohort, 93 GC patients were recruited from the second affiliated hospital of Soochow university. We developed several prediction models based on various convolutional neural networks, and compared their predictive performance. Results: The deep learning model based on the ResNet101 neural network represented sufficient discrimination of EGC. In two validation cohorts, the areas under the curves (AUCs) for the receiver operating characteristic (ROC) curves were 0.993 (95% CI: 0.984-1.000) and 0.968 (95% CI: 0.935-1.000), respectively, and the accuracy was 0.946 and 0.914. Additionally, the deep learning model can also differentiate between mucosa and submucosa tumors of EGC. Conclusions: These results suggested that deep learning classifiers have the potential to be used as a screening tool for EGC, which is crucial in the individualized treatment of EGC patients.

Development and validation of a predictive model combining clinical, radiomics, and deep transfer learning features for lymph node metastasis in early gastric cancer.

Background: This study aims to develop and validate a predictive model combining deep transfer learning, radiomics, and clinical features for lymph node metastasis (LNM) in early gastric cancer (EGC). Materials and methods: This study retrospectively collected 555 patients with EGC, and randomly divided them into two cohorts with a ratio of 7:3 (training cohort, n = 388; internal validation cohort, n = 167). A total of 79 patients with EGC collected from the Second Affiliated Hospital of Soochow University were used as external validation cohort. Pre-trained deep learning networks were used to extract deep transfer learning (DTL) features, and radiomics features were extracted based on hand-crafted features. We employed the Spearman rank correlation test and least absolute shrinkage and selection operator regression for feature selection from the combined features of clinical, radiomics, and DTL features, and then, machine learning classification models including support vector machine, K-nearest neighbor, random decision forests (RF), and XGBoost were trained, and their performance by determining the area under the curve (AUC) were compared. Results: We constructed eight pre-trained transfer learning networks and extracted DTL features, respectively. The results showed that 1,048 DTL features extracted based on the pre-trained Resnet152 network combined in the predictive model had the best performance in discriminating the LNM status of EGC, with an AUC of 0.901 (95% CI: 0.847-0.956) and 0.915 (95% CI: 0.850-0.981) in the internal validation and external validation cohorts, respectively. Conclusion: We first utilized comprehensive multidimensional data based on deep transfer learning, radiomics, and clinical features with a good predictive ability for discriminating the LNM status in EGC, which could provide favorable information when choosing therapy options for individuals with EGC.

CT-based radiomic nomogram for preoperative prediction of DNA mismatch repair deficiency in gastric cancer.

Background: DNA mismatch repair (MMR) deficiency has attracted considerable attention as a predictor of the immunotherapy efficacy of solid tumors, including gastric cancer. We aimed to develop and validate a computed tomography (CT)-based radiomic nomogram for the preoperative prediction of MMR deficiency in gastric cancer (GC). Methods: In this retrospective analysis, 225 and 91 GC patients from two distinct hospital cohorts were included. Cohort 1 was randomly divided into a training cohort (n = 176) and an internal validation cohort (n = 76), whereas cohort 2 was considered an external validation cohort. Based on repeatable radiomic features, a radiomic signature was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. We employed multivariable logistic regression analysis to build a radiomics-based model based on radiomic features and preoperative clinical characteristics. Furthermore, this prediction model was presented as a radiomic nomogram, which was evaluated in the training, internal validation, and external validation cohorts. Results: The radiomic signature composed of 15 robust features showed a significant association with MMR protein status in the training, internal validation, and external validation cohorts (both P-values <0.001). A radiomic nomogram incorporating a radiomic signature and two clinical characteristics (age and CT-reported N stage) represented good discrimination in the training cohort with an AUC of 0.902 (95% CI: 0.853-0.951), in the internal validation cohort with an AUC of 0.972 (95% CI: 0.945-1.000) and in the external validation cohort with an AUC of 0.891 (95% CI: 0.825-0.958). Conclusion: The CT-based radiomic nomogram showed good performance for preoperative prediction of MMR protein status in GC. Furthermore, this model was a noninvasive tool to predict MMR protein status and guide neoadjuvant therapy.

microRNA-15b-5p encapsulated by M2 macrophage-derived extracellular vesicles promotes gastric cancer metastasis by targeting BRMS1 and suppressing DAPK1 transcription.

BACKGROUND: Extracellular vesicles (EVs) derived from tumor-associated macrophages are implicated in the progression and metastasis of gastric cancer (GC) via the transfer of molecular cargo RNAs. We aimed to decipher the impact of microRNA (miR)-15b-5p transferred by M2 macrophage-derived EVs in the metastasis of GC. METHODS: Expression of miR-15b-5p was assessed and the downstream genes of miR-15b-5p were analyzed. GC cells were subjected to gain- and loss-of function experiments for miR-15b-5p, BRMS1, and DAPK1. M2 macrophage-derived EVs were extracted, identified, and subjected to co-culture with GC cells and their biological behaviors were analyzed. A lung metastasis model in nude mice was established to determine the effects of miR-15b-5p on tumor metastasis in vivo. RESULTS: miR-15b-5p was upregulated in GC tissues and cells as well as in M2 macrophage-derived EVs. miR-15b-5p promoted the proliferative and invasive potentials, and epithelial-mesenchymal transition (EMT) of GC cells. M2 macrophage-derived EVs could transfer miR-15b-5p into GC cells where it targeted BRMS1 by binding to its 3'UTR. BRMS1 was enriched in the DAPK1 promoter region and promoted its transcription, thereby arresting the proliferative and invasive potentials, and EMT of GC cells. In vivo experiments demonstrated that orthotopic implantation of miR-15b-5p overexpressing GC cells in nude mice displayed led to enhanced tumor metastasis by inhibiting the BRMS1/DAPK1 axis. CONCLUSIONS: Overall, miR-15b-5p delivered by M2 macrophage-derived EVs constitutes a molecular mechanism implicated in the metastasis of GC, and may thus be considered as a novel therapeutic target for its treatment.

A Necroptosis-Related lncRNA-Based Signature to Predict Prognosis and Probe Molecular Characteristics of Stomach Adenocarcinoma.

Background: As a caspase-independent type of cell death, necroptosis plays a significant role in the initiation, and progression of gastric cancer (GC). Numerous studies have confirmed that long non-coding RNAs (lncRNAs) are closely related to the prognosis of patients with GC. However, the relationship between necroptosis and lncRNAs in GC remains unclear. Methods: The molecular profiling data (RNA-sequencing and somatic mutation data) and clinical information of patients with stomach adenocarcinoma (STAD) were retrieved from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was conducted to identify the necroptosis-related lncRNAs (NRLs). Subsequently, univariate Cox regression and LASSO-Cox regression were conducted to establish a 12-NRLs signature in the training set and validate it in the testing set. Finally, the prognostic power of the 12-NRLs signature was appraised via survival analysis, nomogram, Cox regression, clinicopathological characteristics correlation analysis, and the receiver operating characteristic (ROC) curve. Furthermore, correlations between the signature risk score (RS) and immune cell infiltration, immune checkpoint molecules, somatic gene mutations, and anticancer drug sensitivity were analyzed. Results: In the present study, a 12-NRLs signature comprising REPIN1-AS1, UBL7-AS1, LINC00460, LINC02773, CHROMR, LINC01094, FLNB-AS1, ITFG1-AS1, LASTR, PINK1-AS, LINC01638, and PVT1 was developed to improve the prognosis prediction of STAD patients. Unsupervised methods, including principal component analysis and t-distributed stochastic neighbor embedding, confirmed the capability of the present signature to separate samples with RS. Kaplan-Meier and ROC curves revealed that the signature had an acceptable predictive potency in the TCGA training and testing sets. Cox regression and stratified survival analysis indicated that the 12-NRLs signature were risk factors independent of various clinical parameters. Additionally, immune cell infiltration, immune checkpoint molecules, somatic gene mutations, and half-inhibitory concentration differed significantly among different risk subtypes, which implied that the signature could assess the clinical efficacy of chemotherapy and immunotherapy. Conclusion: This 12-NRLs risk signature may help assess the prognosis and molecular features of patients with STAD and improve treatment modalities, thus can be further applied clinically.

RNF114 Silencing Inhibits the Proliferation and Metastasis of Gastric Cancer.

RNF114 (E3 ubiquitin ligase RING finger protein 114) was first identified as a zinc-binding protein that promotes psoriasis development; however, its role in gastric cancer is still unclear. We explored the relationship between RNF114 and gastric cancer using bioinformatics and molecular biology techniques. The results showed that RNF114 was highly expressed in gastric cancer and negatively correlated with the patient's prognosis. Functional assays suggested that RNF114 silencing suppressed the proliferation and metastasis of gastric cancer cells to a certain extent. Further studies showed that RNF114 expression was potentially targeted by miR-218-5p and methylation modification, and mediated downstream EGR1 (early growth response 1) degradation by the ubiquitylation approach. Together, the present results highlight the detrimental effects of RNF114 overexpression in gastric cancer and contribute to a better understanding of the mechanisms underlying RNF114 functionality.

Identification of Circular RNA-Based Immunomodulatory Networks in Colorectal Cancer.

BACKGROUND: Circular RNAs (circRNAs) have been recently proposed as hub molecules in various diseases, especially in tumours. We found that circRNAs derived from ribonuclease P RNA component H1 (RPPH1) were highly expressed in colorectal cancer (CRC) samples from Gene Expression Omnibus (GEO) datasets. OBJECTIVE: We sought to identify new circRNAs derived from RPPH1 and investigate their regulation of the competing endogenous RNA (ceRNA) and RNA binding protein (RBP) networks of CRC immune infiltration. METHODS: The circRNA expression profiles miRNA and mRNA data were extracted from the GEO and The Cancer Genome Atlas (TCGA) datasets, respectively. The differentially expressed (DE) RNAs were identified using R software and online server tools, and the circRNA-miRNA-mRNA and circRNA-protein networks were constructed using Cytoscape. The relationship between targeted genes and immune infiltration was identified using the GEPIA2 and TIMER2 online server tools. RESULTS: A ceRNA network, including eight circRNAs, five miRNAs, and six mRNAs, was revealed. Moreover, a circRNA-protein network, including eight circRNAs and 49 proteins, was established. The targeted genes, ENOX1, NCAM1, SAMD4A, and ZC3H10, are closely related to CRC tumour-infiltrating macrophages. CONCLUSIONS: We analysed the characteristics of circRNA from RPPH1 as competing for endogenous RNA binding miRNA or protein in CRC macrophage infiltration. The results point towards the development of a new diagnostic and therapeutic paradigm for CRC.