TRIM28 Regulates Proliferation of Gastric Cancer Cells Partly Through SRF/IDO1 Axis.

Background: Gastric cancer (GC) is one of the most common malignancies worldwide, with high incidence and mortality rate. Tripartite motif-containing 28 (TRIM28) is an important molecule that affects the occurrence and development of tumors, but its function in GC has not been elucidated clearly. The purpose of this study is to explore the molecular mechanism by which TRIM28 affect the GC. Methods: TRIM28 expression was tested in RNA-seq data from TCGA database, tumor tissue samples from patients and GC cell lines. Genes were silenced or overexpressed by siRNA, lentivirus-mediated shRNA, or plasmids. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to explore the proliferation of GC cells after TRIM28 knockdown. RNA-seq and TCGA database were used to identify target genes. Luciferase report assay was employed to detect the possible mechanism between TRIM28 and Indoleamine 2,3-dioxygenase (IDO1). Tryptophan concentration in cell supernatant was measured using a fluorometric assay kit. MGC-803 and 746T cells were injected into mice to establish xenograft animal models. Results: The expression of TRIM28 was positively correlated with tumor size and poorer prognosis. Upregulation of TRIM28 was observed in GC tissues and cells. In vitro, we proved that knockdown of TRIM28 significantly inhibited the proliferation of GC cells. Then TRIM28 was found to be positively correlated with the expression of IDO1 in GC cells. In accordance with this, tryptophan levels in cell supernatants were increased in TRIM28 knockdown GC cells and overexpression of IDO1 could reverse this phenotype. Serum response factor (SRF), a reported regulator of IDO1, was also regulated by TRIM28 in GC cells. And decreased expression of IDO1 induced by TRIM28 knockdown could be partly reversed through overexpression of serum response factor (SRF) in GC cells. Functional research demonstrated that the expression of IDO1 was increased in GC and IDO1 knockdown could also inhibited the proliferation of GC cells. Furthermore, overexpression of IDO1 could partly reverse proliferation inhibited by TRIM28 knockdown in GC cells. In vivo, knockdown of TRIM28 significantly inhibited the tumor growth and overexpression of IDO1 and SRF both could reverse proliferation inhibited by TRIM28 knockdown. Conclusions: TRIM28 is crucial in the development of GC, and may regulate IDO1 through SRF. TRIM28 promote GC cell proliferation through SRF/IDO1 axis.

The impact of SARS-Cov-2 Omicron infection on short-term outcomes after elective surgery in patients with gastrointestinal cancer.

With the emergence of novel variants, Omicron variant caused a different clinical picture than the previous variants and little evidence was reported regarding perioperative outcomes after Omicron variants. The aim of the study was to evaluate the postoperative outcomes of gastrointestinal cancer patients following Omicron variants infection and also to determine the timing of surgery after infection recovery. A total of 124 patients who underwent gastrointestinal cancer surgery with prior SARS-CoV-2 infection between December 2022 and February 2023 were retrospectively reviewed. 174 cases underwent the same operation during December 2018 and February 2019 as control group. SARS-CoV-2-infected patients were further categorized into three groups based on infected time (1-3 weeks; 4-6 weeks; and ≥ 7 weeks). 90.3% of SARS-CoV-2-infected patients had mild symptoms. The COVID-19 vaccination rate was 71.0%, with a full vaccination rate of 48.4%. There were no significant differences in 30-day morbidity and mortality. There was also no significant difference in pulmonary complications, cardiovascular complications, and surgical complications between the three different diagnosis time groups. In conclusion, reducing waiting time for elective surgery was safe for gastrointestinal cancer patients in the context of an increased transmissibility and milder illness severity with Omicron variant.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) presents a significant global health burden, characterized by a heterogeneous molecular landscape and various genetic and epigenetic alterations. Programmed cell death (PCD) plays a critical role in CRC, offering potential targets for therapy by regulating cell elimination processes that can suppress tumor growth or trigger cancer cell resistance. Understanding the complex interplay between PCD mechanisms and CRC pathogenesis is crucial. This study aims to construct a PCD-related prognostic signature in CRC using machine learning integration, enhancing the precision of CRC prognosis prediction. METHOD: We retrieved expression data and clinical information from the Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Fifteen forms of PCD were identified, and corresponding gene sets were compiled. Machine learning algorithms, including Lasso, Ridge, Enet, StepCox, survivalSVM, CoxBoost, SuperPC, plsRcox, random survival forest (RSF), and gradient boosting machine, were integrated for model construction. The models were validated using six GEO datasets, and the programmed cell death score (PCDS) was established. Further, the model's effectiveness was compared with 109 transcriptome-based CRC prognostic models. RESULT: Our integrated model successfully identified differentially expressed PCD-related genes and stratified CRC samples into four subtypes with distinct prognostic implications. The optimal combination of machine learning models, RSF + Ridge, showed superior performance compared with traditional methods. The PCDS effectively stratified patients into high-risk and low-risk groups, with significant survival differences. Further analysis revealed the prognostic relevance of immune cell types and pathways associated with CRC subtypes. The model also identified hub genes and drug sensitivities relevant to CRC prognosis. CONCLUSION: The current study highlights the potential of integrating machine learning models to enhance the prediction of CRC prognosis. The developed prognostic signature, which is related to PCD, holds promise for personalized and effective therapeutic interventions in CRC.

Genetic association of circulating interleukins and risk of colorectal cancer: A bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have reported that inflammation, especially interleukin family members, plays an important role in the development of colorectal cancer (CRC). However, because of various confounders and the lack of clinical randomized controlled trial, the causal relationship between genetically predicted level of interleukin family and CRC risk has not been fully explained. OBJECTIVE: Bi-directional Mendelian randomization (MR) was conducted to investigate the causal association between interleukin family members and CRC. METHODS: Several genetic variables were extracted as instrumental variables (IVs) from summary data of genome-wide association studies (GWAS) for interleukin and CRC. IVs of interleukin family were obtained from recently published GWAS studies and the summary data of CRC was from FinnGen Biobank. After a series of quality control measures and strict screening, six models were used to evaluate the causal relationship. Pleiotropy, heterogeneity test, and a variety of sensitivity analysis were also used to estimate the robustness of the model results. RESULTS: Genetically predicted higher circulating levels of IL-2 (odds ratio [OR]: 0.76; 95% confidence interval [CI]: 0.63-0.92; p = .0043), IL-17F(OR: 0.78; 95% CI: 0.62-1.00; p = .015), and IL-31 (OR: 0.88; 95% CI: 0.79-0.98; p = .023) were suggestively associated with decreased CRC risk. However, higher level of IL-10 (OR: 1.40; 95% CI: 1.18-1.65; p = .000094) was causally associated with increased risk of CRC. Reverse MR results indicated that the exposure of CRC was suggestively associated with higher levels of IL-36α (OR: 1.23; 95% CI: 1.01-1.49; p = .040) and IL-17RD (OR: 1.22; 95% CI, 1.00-1.48; p = .048) and lower level of IL-13 (OR: 0.78; 95% CI: 0.65-0.95; p = .013). The overall MR results did not provide evidence for causal relationships between other interleukins and CRC (p > .05). CONCLUSION: We offer suggestive evidence supporting a potential causal relationship between circulating interleukins and CRC, underscoring the significance of targeting circulating interleukins as a strategy to mitigate the incidence of CRC.

Application of a New Retraction Method in Laparoscopic Gastrectomy for Gastric Cancer.

BACKGROUND: Better exposition is important for lymph node dissection in the suprapancreatic region and lesser curvature region of the stomach, and digestive tract reconstruction, especially without excellent assistants. PATIENTS AND METHODS: We developed a new laparoscopic retraction method with the use of two internal retractors (TIRs) punctured along with suture. Clinicopathological data, surgical data, and postoperative outcomes were assessed. RESULTS: Of the 143 patients included, 51 underwent surgery with the double-sling suture method and 92 underwent surgery with the TIRs method. Laparoscopic radical gastrectomy was successfully performed in all patients. There were no significant differences in patient characteristics or preoperative data in the 2 groups. The operative time was significantly shorter in the TIR group, but the amount of bleeding did not differ. No retraction-related complications both in clipped tissue and liver occurred in all patients. CONCLUSIONS: Our new retraction technique provided an optimal surgical field and make surgery lower requirements for assistants.

Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/MRI in the Preoperative Diagnosis of Gastric Cancer.

Purpose: Our objective was to compare the value of positron emission tomography/magnetic resonance imaging (PET/MRI) with the new imaging agent [68Ga]Ga-DOTA-FAPI-04 and the traditional imaging agent [18F]FDG for the preoperative diagnosis of gastric cancer. Methods: Forty patients with gastric cancer diagnosed by gastroscopy in gastrointestinal surgery at our hospital from June 2020 to January 2021 were analyzed. All patients underwent simultaneous [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/MRI. The standard uptake value (SUV), fat removal standard uptake value (SUL), and diagnostic sensitivity, specificity, and accuracy for primary and metastatic lesions were compared, and their diagnostic value for different lymph node dissection stages was analyzed. Results: The median age of the patients in this cohort was 68 years. Twenty-nine patients underwent surgery, and 11 patients underwent gastroscopic biopsy. The SUVmax of primary lesions in the FDG group and the FAPI group was 5.74 ± 5.09 and 8.06 ± 4.88, respectively (P < 0.01); SULmax values were 3.52 ± 2.80 and 5.64 ± 3.25, respectively (P < 0.01). The SUVmax of metastases in the two groups was 3.81 ± 3.08 and 5.17 ± 2.80, respectively (P < 0.05). The diagnostic sensitivities for primary lesions in the FDG group and the FAPI group were 0.72 and 0.94, respectively (P < 0.05). Combined with postoperative pathological staging, there was no difference in diagnostic sensitivity and specificity of lymph node staging between the FDG and FAPI groups (P > 0.05). Conclusion: Compared with the traditional imaging agent, [68Ga]Ga-DOTA-FAPI-04 has better diagnostic efficiency but no substantial advantage for preoperative lymph node staging.

Assessment of Autologous Blood marker localIzation and intraoperative coLonoscopy localIzation in laparoscopic colorecTal cancer surgery (ABILITY): a randomized controlled trial.

BACKGROUND: Laparoscopic colorectal surgery has been proved to have similar oncological outcomes with open surgery. Due to the lack of tactile perception, surgeons may have misjudgments in laparoscopic colorectal surgery. Therefore, the accurate localization of a tumor before surgery is important, especially in the early stages of cancer. Autologous blood was thought a feasible and safe tattooing agent for preoperative endoscopic localization but its benefits remain controversial. We therefore proposed this randomized trial to the accuracy and safety of autogenous blood localization in small, serosa-negative lesion which will be resected by laparoscopic colectomy. METHODS: The current study is a single-center, open-label, non-inferiority, randomized controlled trial. Eligible participants would be aged 18-80 years and diagnosed with large lateral spreading tumors that could not be treated endoscopically, malignant polyps treated endoscopically that required additional colorectal resection, and serosa-negative malignant colorectal tumors (≤ cT3). A total of 220 patients would be randomly assigned (1:1) to autologous blood group or intraoperative colonoscopy group. The primary outcome is the localization accuracy. The secondary endpoint is adverse events related to endoscopic tattooing. DISCUSSION: This trial will investigate whether autologous blood marker achieves similar localization accuracy and safety in laparoscopic colorectal surgery compared to intraoperative colonoscopy. If our research hypothesis is statistically proved, the rational introduction of autologous blood tattooing in preoperative colonoscopy can help improve identification of the location of tumors for laparoscopic colorectal cancer surgery, performing an optimal resection, and minimizing unnecessary resections of normal tissues, thereby improving the patient's quality of life. Our research data will also provide high quality clinical evidence and data support for the conduction of multicenter phase III clinical trials. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, NCT05597384. Registered 28 October 2022.

Quality and accuracy of gastric cancer related videos in social media videos platforms.

BACKGROUND: Gastric cancer is a major public health problem worldwide. Social media has affected public's daily lives in ways no one ever thought possible. Both TikoTok and its Chinese version Douyin are the most popular short video posting platform. This study aimed to evaluate the quality, accuracy, and completeness of videos for gastric cancer on TikTok and Douyin. METHODS: The terms "gastric cancer" was searched on TikTok in both English and Japanese, and on Douyin in Chinese. The first 100 videos in three languages (website's default setting) were checked. QUality Evaluation Scoring Tool (QUEST) and DISCERN as the instrument for assessing the quality of the information in each video. Content was analysed under six categories (aetiology, anatomy, symptoms, preventions, treatments, and prognosis). The educational value and completeness were evaluated with a checklist developed by the researchers. RESULTS: A total of 78 videos in English, 63 in Japanese, and 99 in Chinese were analyzed. The types of sources were as follows: 6.4% in English, 4.8% in Japanese, and 57.6% in Chinese for health professionals; 93.6% in English, 95.2% in Japanese, and 3.0% in Chinese for private users; none in English and Japanese, but 39.4% in Chinese for other sources. In all, 20.5% in English, 17.5% in Japanese, and 93.9% in Chinese of videos had useful information about gastric cancer. Among the useful videos, the videos published in Chinese had the highest QUEST(p < 0.05) and DISCERN scores(p < 0.05), followed by those published in Japanese. Among the educational videos, prognosis in English (37.5%), symptoms in Japanese (54.5%), and prevention in Chinese (47.3%) were the most frequently covered topic. CONCLUSIONS: TikTok in English and Japanese might not fully meet the gastric cancer information needs of public, but Douyin in Chinese was the opposite.

Characterization of Immune-Related Molecular Subtypes and a Prognostic Signature Correlating With the Response to Immunotherapy in Patients With Gastric Cancer.

Gastric cancer (GC) is a disease characterized by high molecular and phenotypic heterogeneity and represents a leading cause of cancer-related death worldwide. The tumor immune microenvironment (TIME) affects the response to immunotherapy and the prognosis of patients with GC. Explorations of the TIME in GC and characterization of molecular subtypes might enhance personalized treatment and facilitate clinical decision-making. In this study, two molecular subtypes were defined through unsupervised consensus clustering based on immune-related dysregulated genes. Then, patients with different molecular subtypes of GC were shown to have distinct differences in sensitivity to immune checkpoint blockers (ICBs). The immune-related prognostic signature was established utilizing least absolute shrinkage and selection operator (LASSO)-Cox regression analysis. Three independent external cohorts and the IMvigor210 cohort were introduced to validate the robustness of IPRS. scRNA-seq data of GC samples were used to decipher the underlying mechanisms of how IPRS contributes to the TIME. GC biospecimens were collected for RT-qPCR to further validate our findings. In summary, we characterized the abnormal TIME of GC and constructed a reliable immune-related prognostic signature correlating with the response to immunotherapy. This study may provide new strategies for developing individualized treatments for patients with GC.

The Modified Glasgow Prognostic Score Predicts Survival in Gastric Cancer Patients with Normal CEA and CA19-9.

Background: Traditionally, serum CEA and CA19-9 levels are good prognostic factors for gastric cancer. Many gastric cancer patients do not have elevated CEA or CA19-9 levels even at a very advanced stage. This study investigates the significance of the modified Glasgow prognostic score (mGPS) for the survival of gastric cancer patients with normal CEA and CA19-9. Methods: We retrospectively examined 488 curatively resected gastric cancer patients with normal preoperative serum levels of CEA and CA19-9 to evaluate the prognostic ability of mGPS for overall survival. The prognostic significance was analyzed by univariate and multivariate analyses. Results: Age, hemoglobin, white cell count, and neutrophils were each significantly correlated with the mGPS. Multivariate analyses showed that tumor location (HR, 0.803; 95% CI, 0.667-0.966; P=0.020), TNM stage (HR, 2.714; 95% CI, 2.250-3.275; P < 0.001), and mGPS (HR, 1.042; 95% CI, 1.105-1.772; P=0.023) were significantly associated with overall survival. Significant correlations were found between overall survival and mGPS. The Kaplan-Meier analysis demonstrated significant differences among patients with mGPS of 0, 1, and 2 (P < 0.001), with the mortality rate being higher for patients with a higher mGPS. Conclusion: The mGPS can predict survival in gastric cancer patients with normal CEA and CA19-9.

Comprehensive Analysis of the Prognostic Significance of Hsa-miR-100-5p and Its Related Gene Signature in Stomach Adenocarcinoma.

Stomach adenocarcinoma (STAD) is one of the most common cancers in the world. However, the prognosis of STAD remains poor, and the therapeutic effect of chemotherapy and immunotherapy varies from person to person. MicroRNAs (miRNAs) play vital roles in tumor development and metastasis and can be used for cancer diagnosis and prognosis. In this study, hsa-miR-100-5p was identified as the only dysregulated miRNA in STAD samples through an analysis of three miRNA expression matrices. A weighted gene co-expression network analysis (WGCNA) was performed to select hsa-miR-100-5p-related genes. A least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to establish a miR-100-5p-related prognostic signature. Kaplan-Meier analyses, nomograms, and univariate and multivariate Cox regression analyses were used to evaluate the prognostic signature, which was subsequently identified as an independent risk factor for STAD patients. We investigated the tumor immune environment between low- and high-risk groups and found that, among component types, M2 macrophages contributed the most to the difference between these groups. A drug sensitivity analysis suggested that patients with high-risk scores may be more sensitive to docetaxel and cisplatin chemotherapy and that patients in the low-risk group may be more likely to benefit from immunotherapy. Finally, external cohorts were evaluated to validate the robustness of the prognostic signature. In summary, this study may provide new ideas for developing more individualized therapeutic strategies for STAD patients.