DNA methylation biomarkers for predicting lymph node metastasis in colorectal cancer.

Colorectal cancer is one of the most common cancers worldwide. Lymph node metastasis is an important marker of colorectal cancer progression and plays a key role in the evaluation of patient prognosis. Accurate preoperative assessment of lymph node metastasis is crucial for devising appropriate treatment plans. However, current clinical imaging methods have limitations in many aspects. Therefore, the discovery of a method for accurately predicting lymph node metastasis is crucial clinical decision-making. DNA methylation is a common epigenetic modification that can regulate gene expression, which also has an important impact on the development of colorectal cancer. It is considered to be a promising biomarker with good specificity and stability and has promising application in predicting lymph node metastasis in patients with colorectal cancer. This article reviews the characteristics and limitations of currently available methods for predicting lymph node metastasis in patients with colorectal cancer and discusses the role of DNA methylation as a biomarker.

ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer.

Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8+ T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8+ T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.

Corrigendum: A novel ferroptosis-related LncRNA pair prognostic signature predicts immune landscapes and treatment responses for gastric cancer patients.

[This corrects the article DOI: 10.3389/fgene.2022.899419.].

Circulating mtDNA and Impaired Intestinal Barrier after Gastrointestinal Surgery Are Correlated with Postoperative SIRS.

BACKGROUND: This prospective study aimed to explore the correlation between circulating mitochondrial DNA (mtDNA), intestinal barrier function impairment, and postoperative SIRS in patients undergoing gastrointestinal surgery. METHODS: Patients were recruited into this study after signing an informed consent form. Circulating mitochondrial DNA and serum DAO concentrations were measured preoperatively and on day 1 and day 7 postoperatively. Postoperative vitals, routine tests, and biochemical indicators were recorded in detail. RESULTS: Forty patients undergoing gastrointestinal surgery were recruited for and completed this study. Patients were divided into non-fever, fever, and SIRS groups according to their postoperative temperature and other corresponding indexes. The mtDNA was expressed as the number of PCR cycles using three specific sequences. Circulating mtDNA tended to increase in patients after gastrointestinal surgery, but the difference was not significant. Nevertheless, mtDNA in the SIRS group was significantly higher than in patients in the fever and non-fever groups (p < 0.05). Serum DAO showed a trend of increase on the first day after surgery compared with that before surgery, but the difference was not significant (p > 0.05). However, patients in the SIRS group showed a significant increase (p < 0.05) compared with the others. Both circulating mtDNA and DAO showed a downward trend on the seventh day after surgery. CONCLUSIONS: Circulating mtDNA presented a trend of increase after gastrointestinal surgery, and the degree of the increased fold was related to the extent of the inflammation response. In general, the intestinal barrier damage indicator DAO was the same as mtDNA and tended to increase after gastrointestinal surgery and then gradually decrease, which may play a synergistic role in inducing postoperative fever and SIRS.

A Novel Ferroptosis-Related LncRNA Pair Prognostic Signature Predicts Immune Landscapes and Treatment Responses for Gastric Cancer Patients.

Background: The construction of ferroptosis-related lncRNA prognostic models in malignancies has been an intense area of research recently. However, most of the studies focused on the exact expression of lncRNAs and had limited application values. Herein, we aim to establish a novel prognostic model for gastric cancer (GC) patients and discuss its correlation with immune landscapes and treatment responses. Methods: The present study retrieved transcriptional data of GC patients from the Cancer Genome Atlas (TCGA) database. We identified differentially expressed ferroptosis-related lncRNAs between tumor and normal controls of GC samples. Based on a new method of cyclically single pairing, we constructed a 0 or 1 matrix of ferroptosis-related lncRNA pairs (FRLPs). A risk score signature consisting of 10 FRLPs was established using multi-step Cox regression analysis. Next, we performed a series of systematic analyses to investigate the association of the FRLP model and tumor microenvironment, biological function, and treatment responses. An alternative model to the FRLP risk score signature, the gene set score (GS) model was also constructed, which could represent the former when lncRNA expression was not available. Results: We established a novel prognostic signature of 10 ferroptosis-related lncRNA pairs. High-risk patients in our risk score model were characterized by high infiltration of immune cells, upregulated carcinogenic and stromal activities, and heightened sensitivity to a wide range of anti-tumor drugs, whereas low-risk patients were associated with better responses to methotrexate treatment and elevated immunotherapeutic sensitivity. The practicability of the FRLP risk score model was also validated in two independent microarray datasets downloaded from Gene Expression Omnibus (GEO) using the GS model. Finally, two online dynamic nomograms were built to enhance the clinical utility of the study. Conclusion: In this study, we developed a ferroptosis-related lncRNA pair-based risk score model that did not rely on the exact lncRNA expression level. This novel model might provide insights for the accurate prediction and comprehensive management for GC patients.

Identification of Subtypes and a Prognostic Gene Signature in Colon Cancer Using Cell Differentiation Trajectories.

Research on the heterogeneity of colon cancer (CC) cells is limited. This study aimed to explore the CC cell differentiation trajectory and its clinical implication and to construct a prognostic risk scoring (RS) signature based on CC differentiation-related genes (CDRGs). Cell trajectory analysis was conducted on the GSE148345 dataset, and CDRG-based molecular subtypes were identified from the GSE39582 dataset. A CDRG-based prognostic RS signature was constructed using The Cancer Genome Atlas as the training set and GSE39582 as the validation set. Two subsets with distinct differentiation states, involving 40 hub CDRGs regulated by YY1 and EGR2, were identified by single-cell RNA sequencing data, of which subset I was related to hypoxia, metabolic disorders, and inflammation, and subset II was associated with immune responses and ferroptosis. The CDRG-based molecular subtypes could successfully predict the clinical outcomes of the patients, the tumor microenvironment status, the immune infiltration status, and the potential response to immunotherapy and chemotherapy. A nomogram integrating a five-CDRG-based RS signature and prognostic clinicopathological characteristics could successfully predict overall survival, with strong predictive performance and high accuracy. The study emphasizes the relevance of CC cell differentiation for predicting the prognosis and therapeutic response of patients to immunotherapy and chemotherapy and proposes a promising direction for CC treatment and clinical decision-making.

Proximal gastrectomy with double-tract reconstruction versus total gastrectomy for proximal early gastric cancer: A systematic review and meta-analysis.

BACKGROUND: The incidence of proximal gastric cancer in the gastric fundus, cardia, and other parts is increasing rapidly. The purpose of this study was to systematically compare the short-term and long-term clinical effects of proximal gastrectomy with double tract reconstruction (PG-DTR) to total gastrectomy (TG) for proximal early gastric cancer (EGC). METHODS: A systematic review and meta-analysis was conducted through searching the literature in PubMed, Web of Science, Cochrane Library, EMBASE, CNKI, WAN FANG, and VIP databases. All clinical controlled trials and randomized controlled trials (RCTs) of PG-DTR and PG were included. Simultaneously, the relevant data were extracted, and the software RevMan version 5.1 was used for the meta-analysis. RESULTS: Eight studies with a total of 753 patients were eligible for the meta-analysis. There were no significant differences in the operation time, intraoperative blood loss, postoperative hospital stay, early complications (anastomotic fistula and anastomotic bleeding), late complications (reflux symptoms and anastomotic stenosis), and 5-year survival rate between PG-DTR and TG. However, the levels of partial nutritional indicators (vitamin B12 supplements and vitamin B12 deficiency) were significantly higher in the PG-DTR group than in the TG group. CONCLUSION: This study showed ample evidence to suggest that PG-DTR improved the postoperative nutritional status without compromising patient safety while providing the same surgical characteristics and postoperative morbidity as TG.

Identification of stem cell-related subtypes and risk scoring for gastric cancer based on stem genomic profiling.

BACKGROUND: Although numerous studies demonstrate the role of cancer stem cells in occurrence, recurrence, and distant metastases in gastric cancer (GC), little is known about the evolving genetic and epigenetic changes in the stem and progenitor cells. The purpose of this study was to identify the stem cell subtypes in GC and examine their clinical relevance. METHODS: Two publicly available datasets were used to identify GC stem cell subtypes, and consensus clustering was performed by unsupervised machine learning methods. The cancer stem cell (CSC) typing-related risk scoring (RS) model was established through multivariate Cox regression analysis. RESULTS: Cross-platform dataset-based two stable GC stem cell subtypes, namely low stem cell enrichment (SCE_L) and high stem cell enrichment (SCE_H), were prudently identified. Gene set enrichment analysis revealed that the classical oncogenic pathways, immune-related pathways, and regulation of stem cell division were active in SCE_H; ferroptosis, NK cell activation, and post-mutation repair pathways were active in SCE_L. GC stem cell subtypes could accurately predict clinical outcomes in patients, tumor microenvironment cell-infiltration characteristics, somatic mutation landscape, and potential responses to immunotherapy, targeted therapy, and chemotherapy. Additionally, a CSC typing-related RS model was established; it was strongly independent and could accurately predict the patient's overall survival. CONCLUSIONS: This study demonstrated the complex oncogenic mechanisms underlying GC. The findings provide a basis and reference for the diagnosis and treatment of GC.

Pyroptosis Patterns Characterized by Distinct Tumor Microenvironment Infiltration Landscapes in Gastric Cancer.

BACKGROUND: The potential role of pyroptosis in tumor microenvironment (TME) reprogramming and immunotherapy has received increasing attention. As most studies have concentrated on a single TME cell type or a single pyroptosis regulator (PR), the overall TME cell-infiltrating characteristics mediated by the integrated roles of multiple PRs have not been comprehensively recognized. METHODS: This study curated 33 PRs and conducted consensus clustering to identify distinct pyroptosis patterns in gastric cancer (GC) patients. A single-sample gene set enrichment analysis algorithm was used to quantify the infiltration density of TME immune cells and the enrichment scores of well-defined biological signatures. The pyroptosis patterns of individuals were quantified using a principal component analysis algorithm called the pyroptosis score (PS). RESULTS: Three distinct pyroptosis patterns with significant survival differences were identified from 1422 GC samples; these patterns were closely associated with three TME cell-infiltrating landscapes-namely, the immune-inflamed, immune-excluded, and immune-desert phenotypes. The PS model generated on the basis of the pyroptosis pattern-related signature genes could accurately predict the TME status, existing molecular subtypes, genetic variation, therapeutic response, and clinical outcome; among which, a relatively high PS was highly consistent with immune activation, molecular subtypes with survival advantages, high tumor mutation burden, high microsatellite instability, and other favorable characteristics. In particular, from the Cancer Genome Atlas database, the PS model exhibited significant prognostic relevance in a pan-cancer analysis, and patients with a relatively high PS exhibited durable therapeutic advantages and better prognostic benefits in anti-PD1/L1 therapy. CONCLUSIONS: This study demonstrates that pyroptosis is prominently correlated with TME diversity and complexity, and quantification of the pyroptosis patterns of individuals will enhance our cognition of TME infiltration landscapes and help in formulating more effective immunotherapeutic strategies.

A Nomogram for Predicting Multiple Metastases in Metastatic Colorectal Cancer Patients: A Large Population-Based Study.

OBJECTIVES: The present study aims to discover the risk factors of multiple metastases and develop a functional nomogram to forecast multiple metastases in metastatic colorectal cancer (mCRC) patients. METHODS: mCRC cases were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016. Survival times between multiple metastases and single metastasis were compared using Kaplan-Meier analysis and log-rank tests. Risk factors for multiple metastases were determined by univariate and multivariate logistic regression analyses, and a nomogram was developed to forecast the probability of multiple metastases in mCRC patients. We assessed the nomogram performance in terms of discrimination and calibration, including concordance index (C-index), area under the curve (AUC), and decision curve analysis (DCA). Bootstrap resampling was used as an internal verification method, and at the same time we select external data from Renmin Hospital of Wuhan University as independent validation sets. RESULTS: A total of 5,302 cases were included in this study as training group, while 120 cases were as validation group. The patients with single metastasis and multiple metastases were 3,531 and 1,771, respectively. The median overall survival (OS) and cancer-specific survival (CSS) for patients with multiple metastases or single metastasis were 19 vs. 31 months, and 20 vs. 33 months, respectively. Based on the univariate and multivariate analyses, clinicopathological characteristics were associated with number of metastasis and were used to establish nomograms to predict the risk of multiple metastases. The C-indexes and AUC for the forecast of multiple metastases were 0.715 (95% confidence interval (CI), 0.707-0.723), which showed the nomogram had good discrimination and calibration curves of the nomogram showed no significant bias from the reference line, indicating a good degree of calibration. In the validation group, the AUC was 0.734 (95% CI, 0.653-0.834), and calibration curve also showed no significant bias, indicating the favorable effects of our nomogram. CONCLUSIONS: We developed a new nomogram to predict the risk of multiple metastases. The nomogram shows the good prediction effect and can provide assistance for clinical diagnosis and treatment.

Resveratrol Suppresses Severe Acute Pancreatitis-Induced Microcirculation Disturbance through Targeting SIRT1-FOXO1 Axis.

BACKGROUND: Resveratrol (RSV), one of the SIRT1 agonists, has the ability of alleviating severe acute pancreatitis (SAP); however, the concrete protective mechanism remains unknown. It is noteworthy that microcirculation disturbance plays a vital role in SAP, and the SIRT1/FOX1 axis can regulate microcirculation. Therefore, this study is aimed at ascertaining what is the underlying mechanism of the protective effect of RSV on SAP, and whether it is associated with alleviating microcirculation disturbance by regulating the SIRT1/FOX1 axis. METHOD: The model of SAP was induced by retrograde injection of sodium taurodeoxycholate into the bile duct of the rats. The pancreatic wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α ratios; microcirculatory function; and SIRT1 activity were examined. ELISA was used to examine the serum level of lipase, amylase, hemorheology, ET, NO, TXB2, and 6-keto-PGF1α and the content of SIRT1, VEGF, Ang I, and Ang II in the pancreas. RT-PCR was used to examine the mRNA level of VEGF, Ang I, and Ang II. Western blotting was used to detect SIRT1, FOXO1, and acetyl-FOXO1. Immunoprecipitation was used to examine the interaction of SIRT1 and FOXO1. RESULTS: Resveratrol can significantly decrease the expression of lipase, amylase, acetyl-FOXO1, VEGF, Ang II, ET, NO, TXB2, and 6-keto-PGF1α and the ratio of wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α by improving microcirculatory dysfunction and blood viscosity in SAP. Moreover, resveratrol can also promote the interaction of SIRT1 and FOXO1 and increase SIRT1 activity and the expression of SIRT1 and Ang I. The SIRT1 inhibitor, Sirtinol (EX527), obliviously reversed the effects of RSV on SAP. CONCLUSION: Resveratrol can protect rats against SAP, and its protective mechanism is associated with suppressing microcirculation disturbance through activating SIRT1-FOXO1 axis.

Cell differentiation trajectory predicts patient potential immunotherapy response and prognosis in gastric cancer.

The purpose of this study was to investigate the differentiation trajectory of gastric cancer (GC) cells and its clinical relevance and generate a prognostic risk scoring (RS) signature based on GC differentiation-related genes (GDRGs) to predict overall survival (OS). Integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from GC samples were used for analysis. The cell differentiation trajectory analysis identified three subsets with distinct differentiation states, of which subsets I/II were involved in metabolic disorders, subset II were also associated with hypoxia tolerance, and subset III were related to immune-related pathways. GC samples were divided into three GDRG-based molecular subtypes, and it was found that molecular typing based on cell differentiation successfully predicted patient OS, clinicopathological features, immune infiltration status, and immune checkpoint gene expression. An eight-GDRG-based prognostic RS signature was generated, and the OS of the high-risk group was significantly worse than that of the low-risk group. By integrating the GDRG-based RS signature with prognostic clinicopathological characteristics, a clinicopathologic-genomic nomogram was constructed, and this nomogram yielded strong predictive performance and high accuracy. The study highlights the implication of GC cell differentiation for predicting patient clinical outcome and potential immunotherapy response and proposes a promising treatment direction for GC.

Gastrointestinal adenocarcinoma analysis identifies promoter methylation-based cancer subtypes and signatures.

Gastric adenocarcinoma (GAC) and colon adenocarcinoma (CAC) are the most common gastrointestinal cancer subtypes, with a high incidence and mortality. Numerous studies have shown that its occurrence and progression are significantly related to abnormal DNA methylation, especially CpG island methylation. However, little is known about the application of DNA methylation in GAC and CAC. The methylation profiles were accessed from the Cancer Genome Atlas database to identify promoter methylation-based cancer subtypes and signatures for GAC and CAC. Six hypo-methylated clusters for GAC and six hyper-methylated clusters for CAC were separately generated with different OS profiles, tumor progression became worse as the methylation level decreased in GAC or increased in CAC, and hypomethylation in GAC and hypermethylation in CAC were negatively correlated with microsatellite instability. Additionally, the hypo- and hyper-methylated site-based signatures with high accuracy, high efficiency and strong independence can separately predict the OS of GAC and CAC patients. By integrating the methylation-based signatures with prognosis-related clinicopathologic characteristics, two clinicopathologic-epigenetic nomograms were cautiously established with strong predictive performance and high accuracy. Our research indicates that methylation mechanisms differ between GAC and CAC, and provides novel clinical biomarkers for the diagnosis and treatment of GAC and CAC.