Gastric Cancer Research Articles

Prognostic Value and Therapeutic Significance of CCL Chemokines in Gastric Cancer.

Gastric cancer is one of the most common malignant tumours of the gastrointestinal tract, which has a significant negative impact on human health. CCL chemokines play important roles in a variety of tumor microenvironments; nevertheless, gastric cancer has surprisingly limited associations with CCL chemokines. In our study, we comprehensively utilized bioinformatics analysis tools and databases such as cBioPortal, UALCAN, GEPIA, GeneMANIA, STRING, and TRRUST to clarify the clinical significance and biology function of CCL chemokines in gastric cancer. The mRNA expression levels of CCL1/3/4/5/7/8/14/15/18/20/21/22/26 were up-regulated, while the mRNA expression levels of CCL2/11/13/16/17/19/23/24/25/28 were down-regulated. The chemokine significantly associated with the pathological stage of gastric cancer is CCL2/11/19/21. In gastric cancer, the expression level of CCL chemokines was not associated with disease-free survival, but low expression of CCL14 was significantly associated with longer overall survival. Therein, associated with the regulation of CCL chemokines are only 10 transcription factors (RELA, NFKB1, STAT6, IRF3, REL, SPI1, STAT1, STAT3, JUN and SP1). The major biological process and functional enrichment of CCL chemokines are to induce cell-directed migration. These results may indicate that CCL chemokines may be immunotherapeutic targets and promising prognostic biomarkers for gastric cancer.

LOXL1 promotes gastric cancer progression by β-catenin-cyclinD mediated proliferation.

Although much progress has been made in chemotherapy or target therapy for advanced gastric cancer, the prognosis is still poor. It is necessary to screen biomarkers for early diagnosis and prognosis prediction. However, the prognostic value of LOX family in gastric cancer and the underlying molecular mechanisms for promoting the progression of gastric cancer remains unclear. Among five members of LOX family, LOXL1 was the unique independent prognostic risk factor. The nomogram established based on the expression of LOXL1 and other clinical parameters could predict the overall survival rate of gastric cancer. Knockdown (KD) of LOXL1 decreased cell proliferation and led to G1 phase arrest in gastric cells. According to GSEA analysis that LOXL1 was positively correlated with the WNT signaling pathway, in vitro experiment proved that LOXL1-KD reduced the phosphorylation level of β-catenin and the expression of the downstream G1 phase checkpoint CCND1.In Conclusion, LOXL1 has been identified as a potential risk prognostic biomarker for gastric cancer by promoting gastric cancer proliferation via WNT/β-catenin/cyclinD1 pathway.

Inhibition of PI3K/Akt/mTOR Signaling Pathway Suppresses 5-Fluorouracil Resistance in Gastric Cancer.

At present, 5-Fluorouracil (5-FU) is a crucial anti-cancer drug and is widely used for the treatment of various carcinomas, including gastric cancer (GC). The resistance of GC cells to 5-FU is still a matter of great concern. To illustrate the role of PI3K/Akt/mTOR signaling in regulating the cell cycle progression and migration of 5-FU-resistant GC cells. After the establishment of drug-resistant GC cell lines, the effects of 5-FU and/or BEZ235 (the dual inhibitor of PI3K and mTOR) on the activity of parental or drug-resistant GC cells were explored. The viability and localization of GC cells (MKN-45 and MKN-74) and their drug-resistant cells (MKN-45/R and MKN-74/R) were assessed using MTT assays and immunofluorescence staining. The impacts of 5-FU and/or BEZ235 on GC cell cycle progression and cell migration were assessed via flow cytometry analyses and wound healing assays, respectively. GC tissues were collected from patients with GC sensitive or refractory to 5-FU chemotherapy. RT-qPCR and western blot were conducted to measure PI3K, AKT, and mTOR levels in GC cells or tissues. After 5-FU treatment, GC cells displayed 5-FU resistance and the viability of drug-resistant cells (MKN-45/R and MKN-74/R) was higher than that of parental cells (MKN-45 and MKN-74). The IC50 values for MKN-45 and MKN-45/R were 8.93 ug/ml and 140 ug/ml, and the values for MKN-74 and MKN-74/R were 3.93 ug/ml and 114.29 ug/ml. Additionally, the PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. BEZ235 promoted cell cycle arrest and suppressed the migration of GC cells. Moreover, the combination of BEZ235 and 5-FU led to more effective suppressive influence on cell cycle progression and cell migration relative to the single 5-FU or BEZ235 treatment. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells.

A nomogram for predicting nutritional risk before gastric cancer surgery.

Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Patients with GC have higher nutritional risk. This study aimed to construct a nomogram model for predicting preoperative nutritional risk in patients with GC in order to assess preoperative nutritional risk in patients more precisely. Patients diagnosed with GC and undergoing surgical treatment were included in this study. Data was collected through clinical information, laboratory testing, and radiomics-derived characteristics. Least absolute shrinkage selection operator (LASSO) regression analysis and multi-variable logistic regression were employed to construct a clinical prediction model, which takes the form of a logistic nomogram. The effectiveness of the nomogram model was evaluated using receiver operat-ing characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). A total of three predictors, namely body mass index (BMI), hemoglobin (Hb) and radiomics characteristic score (Radscore) were identified by LASSO regression analysis from a total of 21 variables studied. The model constructed using these three predictors displayed medium prediction ability. The area under the ROC curve was 0.895 (95% CI 0.844-0.945) in the training set, with a cutoff value of 0.651, precision of 0.957, and sensitivity of 0.718. In the validation set, it was 0.880 (95% CI 0.806-0.954), with a cutoff value of 0.655, precision of 0.930, and sensitivity of 0.698. DCA also confirmed the clinical benefit of the combined model. This simple and dependable nomogram model for clinical prediction can assist physicians in assessing preoperative nutritional risk in GC patients in a time-efficient and accurate manner to facilitate early identification and diagnosis.

Crosstalk Between Cancer-associated Fibroblasts and Myeloid Cells Shapes the Heterogeneous Microenvironment of Gastric Cancer.

Targeted therapies have improved the clinical outcomes of most patients with cancer. However, the heterogeneity of gastric cancer remains a major hurdle for precision treatment. Further investigations into tumor microenvironment heterogeneity are required to resolve these problems. In this study, bioinformatic analyses, including metabolism analysis, pathway enrichment, differentiation trajectory inference, regulatory network construction, and survival analysis, were applied to gain a comprehensive understanding of tumor microenvironment biology within gastric cancer using single-cell RNA-seq and public datasets and experiments were carried out to confirm the conclusions of these analyses. We profiled heterogeneous single-cell atlases and identified eight cell populations with differential expression patterns. We identified two cancer-associated fibroblasts (CAFs) subtypes, with particular emphasis on the role of inflammatory cancer-associated fibroblasts (iCAFs) in EMT and lipid metabolic crosstalk within the tumor microenvironment. Notably, we detected two differentiation states of iCAFs that existed in different tissues with discrepant expression of genes involved in immuno-inflammation or ECM remodeling. Moreover, investigation of tumor-infiltrating myeloid cells has revealed the functional diversity of myeloid cell lineages in gastric cancer. Of which a proliferative cell lineage named C1QC+MKI67+TAMs was recognized with high immunosuppressive capacities, suggesting it has immune suppression and cell proliferation functions in the tumor niche. Finally, we explored regulatory networks based on ligand-receptor pairs and found crucial pro-tumor crosstalk between CAFs and myeloid cells in the tumor microenvironment (TME). These findings provide insights for future cancer treatments and drug discovery.

Utilization and validation of dried blood spot-based metabolomics in plasma-derived diagnostic models

Metabolomics has rapidly advanced in life sciences, enhancing our understanding of physiological conditions. Plasma stands out as a predominant sample type in metabolomics studies. Dried blood spot (DBS) has been recognized as a valuable strategy due to its unique characteristics, such as minimal invasiveness, small sample volume, and easy transport. Most large cohort studies construct the diagnostic model using plasma-based metabolomics rather than DBS. However, the comparability of metabolite measurements between DBS and plasma samples, as well as the integration of DBS-based metabolomics into established plasma-derived diagnostic models, remains unclear. We collected plasma and DBS samples from the same 12 healthy controls under fasting and non-fasting conditions and performed ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics. We identified 277 metabolites present in both plasma and DBS samples, with 229 (82.7 %) showing a strong correlation between the two sample types. Furthermore, pre-processing datasets from plasma and DBS samples before combining them effectively diminished inconsistencies between plasma- and DBS-based metabolomics without compromising the inherent classification within the data. For the clinical application, the plasma samples were obtained from the gastric cancer patients (n = 204) and the healthy controls (n = 128) to serve as the training cohorts. Additionally, DBS samples were collected from different participants of gastric cancer (n = 19) and healthy controls (n = 12) to validate the diagnostic model. Finally, DBS-based metabolomics were integrated into established plasma-derived gastric cancer diagnostic models, yielding an area under the ROC curve (AUC) of 0.934. Overall, incorporating DBS-based metabolomics into an established plasma-derived diagnostic model holds promise, offering valuable opportunities and insights for diagnostic research and clinical practice.

Microplastics and Cancer Progression: A Comparative Study of 2D and 3D Gastric Cancer Models Using ISO-Compliant Protocols

Microplastics have emerged as a significant global environmental concern, yet the absence of standardized protocols for assessing their toxicity remains a challenge. To address this gap, we applied the ISO 10993-5:2009 and ISO 10993-12:2012 standards for the first time to evaluate the effects of microplastics on cancer progression. Our study utilized both two-dimensional and three-dimensional models of gastric cancer to investigate the potential role of microplastics in promoting cancer growth. The MTT assay results revealed that the highest concentrations of polyethylene microplastics (PE-MPs) and polypropylene microplastics (PP-MPs) enhanced the proliferation of gastric cancer cells at both 24 and 72 hours. After 24 hours, AGS cells treated with PE-MPs and PP-MPs exhibited increased viability, reaching 116.08% ± 15.55 and 118.78% ± 13.96, respectively; however, this increase was not statistically significant. In contrast, after 72 hours, AGS cells showed significantly enhanced growth, with viability reaching 122.37% ± 9.28 for PE-MPs and 131.51% ± 3.05 for PP-MPs (p < 0.001). In the three-dimensional model, live/dead staining results after seven days indicated that spheroids exposed to microplastics demonstrated greater cell survival compared to the control group. The percentage area growth of spheroids was 7.93% ± 1.5 for the control, 13.93% ± 4.85 for PE-MPs, and 19.59% ± 1.61 for PP-MPs, with the increase in PP-MPs being statistically significant (p < 0.05). Additionally, microplastics did not penetrate the three-dimensional gastric cancer within seven days. This research highlights the potential impact of microplastics on cancer development and introduces a novel methodological approach.

The Roles of Cytoplasmic Polyadenylation Element Binding Protein 1 in Tumorigenesis.

CPEB1 is an alternative polyadenylation binding protein that promotes or suppresses the expression of related mRNAs and proteins by binding to a highly conserved Cytoplasmic Polyadenylation Element (CPE) in the mRNAs 3'UTR. It is found to express abnormally in multiple tumors and affect tumorigenesis through many pathways. This review summarizes the functions and mechanisms of CPEB1 in a variety of cancers and suggests new directions for future related treatments. A total of 95 articles were eligible for inclusion based on the year, quality of the research, and the strength of association with CPEB1. In this review, current research about how CPEB1 affects the initiation and progression of glioblastoma, breast cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, and melanoma are dissected, and the biomedical functions and mechanisms are summarized. CPEB1 mostly presents as a tumor suppressor for breast cancer, endometrial carcinoma, hepatocellular carcinoma, non-small cell lung cancer, prostate cancer, and melanoma. However, for glioblastoma, gastric cancer, and colorectal cancer, CPEB1 exhibts two opposing properties of tumorigenesis, either promoting or inhibiting it. CPEB1 is likely to serve as a target and dynamic detection index or prognostic indicator for its function of apoptosis, activity, proliferation, migration, invasion, stemness, drug resistance, and even ferroptosis in various cancers.

Cellulose nanocrystals/cellulose nanofibrils-combined astaxanthin nanoemulsion for reinforcement of targeted tumor delivery of gastric cancer cells

Nanoemulsion based nanomaterial (NE) was carried out in the present study to evaluate the efficacy and its antitumor potential of the gastric cancer cells. NE was prepared with astaxanthin/alpha-tocopherol- cellulose nanocrystals/cellulose nanofibrils based nanoemulsions for gastric cancer treatment. The cytotoxic potential was tested against cancer cells and evaluated in terms of its cell proliferation, migration, and cellular uptake by the standard methods. NE was examined for its synergetic effect with photodynamic therapy (PDT) in a xenograft mouse model. The results confirmed the synergetic effect of PDT and NEs in the in vivo animal model. The regulated expression of proteins manifested the reduced toxicity and inhibition of cell proliferation and migration. The antitumor study showed that NE inhibited the growth of human colon cancer in vivo. Immunohistological analysis confirmed the regulation of PI3K/AKT signaling pathway. The present study demonstrates that NEs can enhance anti-cancer effect against human gastric cancer through the immunomodulatory signaling pathway.

Multi-omics Combined with Machine Learning Facilitating the Diagnosis of Gastric Cancer.

Gastric cancer (GC) is a highly intricate gastrointestinal malignancy. Early detection of gastric cancer forms the cornerstone of precision medicine. Several studies have been conducted to investigate early biomarkers of gastric cancer using genomics, transcriptomics, proteomics, and metabolomics, respectively. However, endogenous substances associated with various omics are concurrently altered during gastric cancer development. Furthermore, environmental exposures and family history can also induce modifications in endogenous substances. Therefore, in this study, we primarily investigated alterations in DNA mutation, DNA methylation, mRNA, lncRNA, miRNA, circRNA, and protein, as well as glucose, amino acid, nucleotide, and lipid metabolism levels in the context of GC development, employing genomics, transcriptomics, proteomics, and metabolomics. Additionally, we elucidate the impact of exposure factors, including HP, EBV, nitrosamines, smoking, alcohol consumption, and family history, on diagnostic biomarkers of gastric cancer. Lastly, we provide a summary of the application of machine learning in integrating multi-omics data. Thus, this review aims to elucidate: i) the biomarkers of gastric cancer related to genomics, transcriptomics, proteomics, and metabolomics; ii) the influence of environmental exposure and family history on multiomics data; iii) the integrated analysis of multi-omics data using machine learning techniques.

Fatty Acid Metabolism Signature Contributes to the Molecular Diagnosis of a Malignant Gastric Cancer Subtype with Poor Prognosis and Lower Mutation Burden.

Gastric cancer (GC) is a common gastrointestinal tumor with high morbidity and mortality. Fatty acid metabolism (FAM) contributes to GC development. Patents have been issued for the use of compositions comprising fatty acid analogues for the treatment of many clinical conditions. However, its clinical significance and its relationship with tumor-related mutations have not been thoroughly discovered. This study was conducted to analyze and explore FAM-related genes' molecular characteristics, prognostic significance, and association with tumor- related mutations. The gastric adenocarcinoma's transcriptome, clinical data, and tumor mutation load (TMB) data were downloaded from TCGA and GEO databases. The differentially expressed FAM genes (FAM DEGs) between cancer and control samples were screened, and their correlation with TMB and survival was analyzed. A PPI network of FAM DEGs was constructed, and a downscaling clustering analysis was performed based on the expression of the FAM DEGs. Further immuno- infiltration and GO/KEGG enrichment analyses of the identified FAM clusters were performed to explore their heterogeneity in biological functions. The effects of FAM score and gastric cancer (STAD) on TMB, MSI, survival prognosis, and drug sensitivity were jointly analyzed, and finally, a single-gene analysis of the obtained core targets was performed. Through differential analysis, 68 FAM DEGs were obtained, and they were highly associated with STAD tumor mutation load. In addition, a high FAM DEGs CNV rate was observed. The PPI network showed a complex mutual correlation between the FAM DEGs. Consensus clustering classified the patients into three clusters based on the FAM DEGs, and the clusters presented different survival rates. The GSVA and immune infiltration analysis revealed that metabolism, apoptosis, and immune infiltration-related pathways were variated. In addition, FAM genes, STAD prognostic risk genes, and PCA scores were closely associated with the survival status of STAD patients. FAM score was closely correlated with STAD TMB, MSI, and immunotherapy, and the TMB values in the low FAM score group were significantly higher than those in the high FAM score group. Finally, combining the above results, it was found that the core gene PTGS1 performed best in predicting STAD survival prognosis and TMB/MSI/immunotherapy. Fatty acid metabolism genes affect the development of gastric adenocarcinoma and can predict the survival prognosis, tumor mutational load characteristics, and drug therapy sensitivity of STAD patients, which can help explore more effective immunotherapy targets for GC.

Molecular characterization and biomarker discovery in gastric cancer progression through transcriptome meta-analysis

Gastric cancer (GC) is a leading cause of cancer-related deaths globally. It is a multifactorial, molecularly heterogeneous disease whose carcinogenic patterns are not yet well established, requiring the development of new tools for better understanding and identifying gastric carcinogenesis. From this point of view, this study aims to compare transcriptome profiles from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) and a human-merged dataset to identify potential biomarkers and therapeutic targets. Principal component analysis (PCA) revealed shared and distinct gene expression patterns between datasets. Differential expression analysis identified key genes with altered expression across non-malignant and malignant samples. Six genes, including SERPINE1 and CLDN9, were significantly associated with patient survival. The findings underscore the molecular diversity of GC and highlight novel biomarkers for early diagnosis and therapeutic strategies. Further validation in clinical specimens is necessary.

Prognosis and Clinical Significance of Piezo2 in Tumor: A Meta-analysis and Database Validation.

The objective of this study is to assess the correlation between Piezo2 and tumors through a comprehensive meta-analysis and database validation. Case-control studies investigating the association between Piezo2 and tumors were obtained from various databases, including China National Knowledge Infrastructure (CNKI), SinoMed, Embase, Web of Science, The Cochrane Library, and PubMed. The search was performed from the inception of each database up until May 2023. Two researchers independently screened the literature, extracted data, and assessed the quality of the included studies. Metaanalysis of the included literature was conducted using Stata 12.0 software. Additionally, the Gene Expression Profiling Interactive Analysis (GEPIA) database predicted a correlation between Piezo2 expression and prognostic value in tumor patients. A total of three studies, involving a combined sample size of 392 participants, were included in the meta-analysis. The findings revealed that the expression level of Piezo2 in tumor patients was not significantly associated with age, gender, or tumor size. However, it was found to be positively correlated with lymphatic invasion (OR = 7.89, 95%CI: 3.96-15.73) and negatively correlated with invasion depth (OR = 0.17, 95%CI: 0.06-0.47), TNM stage (OR = 0.48, 95%CI: 0.27-0.87), and histological grade (OR = 0.40, 95%CI: 0.21-0.77). Confirming these findings, the GEPIA database indicated that high expression of Piezo2 was associated with poor prognosis of disease-free survival in patients with colon adenocarcinoma (HR = 1.6, P = 0.049) and gastric cancer (HR = 1.6, P = 0.017). Piezo2 may be associated with poor prognosis and clinicopathological parameters in tumor patients.

FAT4 Mutation is Related to Tumor Mutation Burden and Favorable Prognosis in Gastric Cancer.

This study aimed to investigate the frequently mutated genes in Gastric Cancer (GC), assess their association with Tumor Mutation Burden (TMB) and the patients' survival, and identify the potential biomarkers for tailored therapy. Simple somatic mutation data of GC were collected from the TCGA and ICGC databases. The high-frequency mutated genes were identified from both datasets. The samples were initially dichotomized into wild-type and mutation groups based on the status of overlapping genes. TMB difference between the two groups was evaluated by the Mann-Whitney U-test. Survival difference between the two groups was compared by the Kaplan-Meier method with a log-rank test. The prognostic value of the target gene was assessed by the Cox proportional hazards model. The signaling pathways involved in FAT4 mutation were identified by Gene Set Enrichment Analysis (GSEA). The fractions of different tumor-infiltrating immune cells were calculated by the CIBERSORT algorithm. 21 overlapping genes with frequent mutation were identified in both datasets. Mutation of these genes was significantly associated with higher TMB (P<0.05) in GC. The survival of the FAT4 mutation group was superior to the wild-type group. FAT4 mutation was also identified as an independent favorable prognostic factor for the GC patients. GSEA indicated that FAT4 mutation activated the signaling pathways involved in energy metabolism. Finally, CD4 memory-activated T cells, follicular helper T cells, and gamma delta T cells were significantly more enriched, while naïve B cells and regulatory T cells (Tregs) were significantly less enriched in the FAT4 mutation group (P<0.05). FAT4 mutation is relevant to TMB and favorable prognosis in GC, which may become a useful biomarker for immunotherapy of GC patients.

Risk stratification models incorporating oxidative stress factors to predict survival and recurrence in patients with gastric cancer after radical gastrectomy: a real-world multicenter study

BackgroundOxidative stress significantly influences the development and progression of gastric cancer (GC). It remains unreported whether incorporating oxidative stress factors into nomograms can improve the predictive accuracy for survival and recurrence risk in GC patients. Methods3498 GC patients who underwent radical gastrectomy between 2009 and 2017 were enrolled and randomly divided into training cohort (TC) and internal validation cohort (IVC). Cox regression analysis model was used to evaluate six preoperative oxidative stress indicators to formulate the Systemic oxidative stress Score (SOSS). Two nomograms based on SOSS was constructed by multivariate Cox regression and validated using 322 patients from another two hospitals. ResultsA total of 3820 patients were included. The SOSS, composed of three preoperative indicators—fibrinogen, albumin, and cholesterol—was an independent prognostic factor for both overall survival (OS) and disease-free survival (DFS). The two nomograms based on SOSS showed a significantly higher AUC than the pTNM stage (OS: 0.830 vs. 0.778, DFS: 0.824 vs. 0.775, all P < 0.001) and were validated in the IVC and EVC (all P<0.001). The local recurrence rate, peritoneal recurrence rate, distant recurrence rate and multiple recurrence rate in high-risk group were significantly higher than those in low-risk group (P < 0.05). ConclusionsThe two novel nomograms based on SOSS which was a combination score of three preoperative blood indicators, demonstrated outstanding predictive abilities for both survival and recurrence in GC patients with different risk groups, which may potentially improve survival through perioperatively active intervention strategies and individualized postoperatively close surveillance.

Antibacterial and antibiofilm agents in the group of xanthone derivatives with piperazine moiety active against drug-resistant Helicobacter pylori strains

Helicobacter pylori (H. pylori) cause chronic inflammation of the gastric mucosa which can lead to epithelial atrophy and metaplasia resulting in peptic ulcer disease and gastric cancer. The increasing resistance of H. pylori to antibiotics and chemotherapeutics used to treat the infection is a serious problem. However, it has been confirmed that the introduction of effective anti-H. pylori therapy can prevent the progression to cancerous changes. This problem calls for the search for new and effective therapies. Xanthones are a group of compounds with extensive biological activities, including antibacterial activity, also against H. pylori. Addressing this issue, the aim of the study was to evaluate the potential of a group of 13 xanthone derivatives against susceptible and resistant H. pylori strains. Moreover, our objective was to conduct tests aimed at determining their ability to inhibit biofilm formation.The antimicrobial evaluation revealed that benzylpiperazine coupled at the C-2 position to xanthone (compounds C11 and C12) had good selective bacteriostatic activity against reference and clinical H. pylori strains (MBC/MIC ratio >4) but with no activity against other bacteria such as Staphylococcus aureus, Escherichia coli, and Lactobacillus paracasei. Analysis of the activity of compounds C11 and C12 against the biofilm formed by H. pylori strain ATCC 700684, and the clinical strain showed that these compounds caused a significant reduction in the amount of biofilm produced (5–20×). Moreover, cell viability analysis confirmed a 3–4× reduction in the viability of cells forming biofilm after treatment with C11 and C12. Finally,both compounds did not impair human fibroblast viability at tested concentrations and were not mutagenic in the Ames test. Therefore, they could be promising leads as antibacterial candidates for multidrug-resistant strains of H. pylori.

Role of NADPH Quinone Reductase 1 (NQO1) Polymorphism in Prevention, Diagnosis, and Treatment of Gastrointestinal Cancers.

Most cancer deaths are related to gastrointestinal (GI) cancers. Several environmental and genetic factors are effective in the occurrence of GI cancers, such as esophageal, stomach, colorectal, liver, and pancreatic cancers. In addition to risk factors related to lifestyle, reactive oxygen species (ROS) also play a role in GI cancers, and an increase in the amount of free radicals can lead to oxidative stress and increase the probability of malignancies. NQO1 is part of the body's antioxidant defense system that protects cells against mutagenesis and carcinogenesis. NQO1 is responsible for reducing quinones to hydroquinone and preventing the generation of ROS by catalyzing the reaction. The existence of single nucleotide polymorphisms (SNPs) of NADPH Quinone Reductase 1 (NQO1), such as 609C>T NQO1, leads to a decrease in NQO1 enzyme activity. Some NQO1 polymorphisms may increase the risk of gastrointestinal cancer. So, the C609T polymorphism in the NQO1 gene has been found to be effective in causing gastrointestinal cancers. On the other hand, it is very important to know the role of biomarkers in the prognosis and management of cancer treatment. Therefore, this study investigated the role of NQO1 as a biomarker in the management of gastrointestinal cancers (prevention, diagnosis and treatment).

Synthesis of Chalcones, Screening In silico and In vitro and Evaluation of Helicobacter pylori Adhesion by Molecular Docking.

We synthetized 10 hydroxylated and methoxylated chalcones and evaluated them targeting MMP-9 inhibition, looking for the rate of adhesion of H. pylori in gastric cells, and then, reduction of the inflammatory response as alternative therapeutic agents for controlling the infection. Helicobacter pylori is a Gram-negative bacterium that chronically infects the human stomach, a risk factor for the development of inflammatory gastrointestinal diseases, including cancer, and is classified as a group I carcinogen. It is estimated that it infects around 45% of the global population and that the persistence of the infection is related to the adhesion of the bacteria in the gastric epithelium. The progression of gastric lesions to cancer is connected to the activation of the NF-κB and MAPK pathways, especially in cagA+ strains, which are related to increased expression of MMP-9. The activation of these metalloproteinases (MMPs) contributes to the adhesion of the bacterium in gastric cells and the evolving stages of cancer, such as enabling metastasis. Due to the increasing resistance to the current therapy protocols, the search for alternative targets and candidate molecules is necessary. In this way, controlling adhesion seems to be a suitable option since it is a crucial step in the installation of the bacterium in the gastric environment. Synthetize ten hydroxylated and methoxylated chalcones. Assess their anti-H. pylori potential, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC). Evaluate their cytotoxicity in AGS cells and selectivity with L-929 cells. Analyze the results and correlate them with in silico predictions to evaluate potential anti-adhesive properties for the chalcones against H. pylori. The chalcones were synthetized by Claisen-Schmidt condensation using Ba(OH)2 or LiOH as catalysts. Predictive in silico assays in PASS Online, tanimoto similarity, ADME properties and molecular docking in MMP-9 (PDB code: 6ESM) were performed. The in vitro assays carried out were the cell viability in gastric adenocarcinoma cells (AGS) and fibroblasts (L-929) by the MMT method and anti-H. pylori, by the broth microdilution method, through the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Ten chalcones were synthesized through Claisen-Schimdt condensation with yields of 10 to 52% and characterized by 1H and 13C nuclear magnetic resonance (NMR) and mass spectrometry (MS). in silico data revealed the possibility of anti-H. pylori, anti-inflammatory, and MMP-9 inhibition for the chalcones. Chalcone 9 showed the best growth inhibition values for MIC and MBC, at 1 μg/mL and 2 μg/mL, respectively. Chalcones 14 and 15 likewise demonstrated excellent inhibitory results, being 2 μg/mL for both MIC and MBC. Additionally, 15 had the best MMP-9 inhibition score. Despite not corroborating the in silico findings, chalcones 10, 13, and 18 showed good cytotoxicity and the best selectivity indices. All compounds exhibited strong activity against H. pylori, specially 15. The predicted MMP-9 inhibition by molecular docking added to the reasonable SI and CI50 values for 15 and the satisfactory reduction in the rate of survival of the bacteria, reveals that it may be acting synergically to reduce the inflammatory response and the possibilities for developing a tumor by inhibiting both bacteria and malignant cells.

Utility of near-infrared fluorescent clip for the robot-assisted gastrectomy: Report of 2 cases (case series)

Introduction and importanceThe importance of preoperative tumor site marking has increased over the years, as the method of intraoperative primary lesion identification and determination of resection margins is one factor determining whether oncological safety and function-preserving gastrectomy are possible during surgery. We hypothesize that preoperative placement of the near-infrared fluorescent (NIRF) clip, ZEOCLIP FS, near the oral incision line of the gastric tumor will allow for Firefly recognition of the NIRF clip on da Vinci during surgery and easy determination of the tumor location and incision line. Hence, we report on two cases in which the procedure was performed. Case presentationCase 1: A 62-year-old woman was diagnosed with early gastric cancer of 35 mm in size located in the greater curvature of the gastric angle and underwent robot-assisted distal gastrectomy. NIRF clips were placed around the negative biopsy-confirmed area on the tumor's oral side by endoscopy on the day before surgery. The clips were identified intraoperatively in Firefly mode, and we performed gastrectomy without using an intraoperative endoscope. Case 2: A 60-year-old man was diagnosed with early gastric cancer 40 mm in size on the anterior wall of the gastric angle and underwent robot-assisted distal gastrectomy. Similarly, NIRF clips were placed around the site of negative biopsy confirmation the day before surgery. NIRF clips were identified, and we performed gastrectomy. Clinical discussionThe time taken to mark the gastric resection line after activating the Firefly imaging system was 120 and 154 s, respectively, and intraoperative endoscopy was not required. The advantage of our two-step method is that a surgeon can mark the clips the day before the surgery, even if they are not endoscopists. Increasing the recognition rate of fluorescent clips and preventing their remains are future issues. ConclusionBased on the results of the above two cases, ZEOCLIP FS is influential in determining the tumor's location and the resection line.

Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds.

Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mice xenograft assay, western blotting. 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which had better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP in a dose-dependent manner. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs. In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.