Colonization of the human stomach with cag pathogenicity island (PAI)-positive Helicobacter pylori strains is associated with increased gastric cancer risk compared to colonization with cag PAI-negative strains. To evaluate the contributions of the Cag type IV secretion system (T4SS) and CagA (a secreted bacterial oncoprotein) to gastric molecular alterations relevant for carcinogenesis, we infected Mongolian gerbils with a Cag T4SS-positive wild-type (WT) H. pylori strain, one of two Cag T4SS mutant strains (∆cagT or ∆cagY), or a ∆cagA mutant for 12 weeks. Histologic staining revealed a biphasic distribution of gastric inflammation severity in WT-infected animals and minimal inflammation in animals infected with mutant strains. Atrophic gastritis (a premalignant condition), dysplasia, and gastric adenocarcinoma were only detected in WT-infected animals with high inflammation scores. Transcriptional profiling, liquid chromatography-tandem mass spectrometry analysis of micro-extracted tryptic peptides, and imaging mass spectrometry revealed more than a thousand molecular alterations in gastric tissues from WT-infected animals with high inflammation scores compared to uninfected tissues and few alterations in tissues from other groups of infected animals. Proteins with altered abundance in animals with severe Cag T4SS-induced inflammation mapped to multiple pathways, including the complement/coagulation cascade and proteasome pathway. Proteins exhibiting markedly increased abundance in tissues from H. pylori-infected animals with severe inflammation included calprotectin components, proteins involved in proteasome activation, polymeric immunoglobulin receptor (PIGR), interferon-inducible guanylate-binding protein (GBP2), lactoferrin, lysozyme, superoxide dismutase, and eosinophil peroxidase. These results demonstrate key roles for CagA and Cag T4SS activity in promoting gastric mucosal inflammation, transcriptional alterations, and proteomic alterations relevant to gastric carcinogenesis.IMPORTANCEHelicobacter pylori colonizes the stomachs of about half of humans worldwide, and its presence is the primary risk factor for the development of stomach cancer. H. pylori strains isolated from humans can be broadly classified into two groups based on whether they contain a chromosomal cag pathogenicity island, which encodes a secreted effector protein (CagA) and components of a type IV secretion system (T4SS). In experiments using a Mongolian gerbil model, we found that severe gastric inflammation and gastric transcriptional and proteomic alterations related to gastric cancer development were detected only in animals infected with a wild-type H. pylori strain containing CagA and an intact Cag T4SS. Mutant strains lacking CagA or Cag T4SS activity successfully colonized the stomach without inducing detectable pathologic host responses. These findings illustrate two different patterns of H. pylori-host interaction.

Guidelines recommend endoscopic surveillance for gastric cancer without therapeutic intervention every 3 years in patients with high-risk gastric intestinal metaplasia (GIM). This study aimed to evaluate the efficacy of radiofrequency ablation (RFA) in eradicating high-risk GIM.

This randomized self-control trial was conducted between June 2020 and February 2023. Patients with histology-verified high-risk GIM were enrolled. The endoscopist performed a biopsy on both the left and right sides of the stomach (five each) by targeting the suspected GIM area where available; otherwise, a random biopsy was taken. Patients were randomized to receive a unilateral RFA on either the left or right side. A repeated RFA on the assigned side was performed every 2-3 months for a total of two to three times. The primary outcome was complete resolution of GIM at 1 year after RFA.

Forty-six patients with a mean age of 66 ± 8 years were analyzed. The complete resolution rate of overall GIM lesions after RFA was significantly higher (49/142; 34/5%) than that in the observation group (29/127; 22.8%, RR = 0.84, 0.73-0.98, p = 0.03). For the subgroup analysis, the complete resolution rate after RFA revealed a significantly higher value than observation only in the incomplete GIM group (24/87; 27.6% vs. 11/82; 13.4%, RR = 0.83, 0.71-0.97, p = 0.02). The percentage of patients with extensive GIM regression after RFA (15/25; 60%) was higher than in the observation group (9/25; 36%) but did not meet statistical significance (RR = 0.62, 0.35-1.09, p = 0.09).

In high-risk GIM, RFA can significantly eradicate incomplete GIM when compared with observation alone.

The discrepancy between endoscopic biopsy pathology and the overall pathology of gastric low-grade intraepithelial neoplasia (LGIN) presents challenges in developing diagnostic and treatment protocols.

To develop a risk prediction model for the pathological upgrading of gastric LGIN to aid clinical diagnosis and treatment.

We retrospectively analyzed data from patients newly diagnosed with gastric LGIN who underwent complete endoscopic resection within 6 months at the First Medical Center of Chinese People's Liberation Army General Hospital between January 2008 and December 2023. A risk prediction model for the pathological progression of gastric LGIN was constructed and evaluated for accuracy and clinical applicability.

A total of 171 patients were included in this study: 93 patients with high-grade intraepithelial neoplasia or early gastric cancer and 78 with LGIN. The logistic stepwise regression model demonstrated a sensitivity and specificity of 0.868 and 0.800, respectively, while the least absolute shrinkage and selection operator (LASSO) regression model showed sensitivity and specificity values of 0.842 and 0.840, respectively. The area under the curve (AUC) for the logistic model was 0.896, slightly lower than the AUC of 0.904 for the LASSO model. Internal validation with 30% of the data yielded AUC scores of 0.908 for the logistic model and 0.905 for the LASSO model. The LASSO model provided greater utility in clinical decision-making.

A risk prediction model for the pathological upgrading of gastric LGIN based on white-light and magnifying endoscopic features can accurately and effectively guide clinical diagnosis and treatment.

Helicobacter pylori infection is a significant contributing factor of gastric cancer. Metachronous neoplasms also pose a risk. The mechanism underlying the impact of H. pylori eradication on preventing metachronous gastric cancer is unclear. This study aimed to investigate immunity changes in gastric mucosa after H. pylori eradication and to identify mechanisms preventing metachronous recurrence.

Patients diagnosed with gastric neoplasm and H. pylori infection, who underwent endoscopic resection, were included. Thirty-six cases of metachronous neoplasms occurring after eradication (metachronous group) were compared to 36 controls matched for age, sex, atrophy, and metaplasia (control group). Histological features and immunohistochemical staining for T-cell (CD3, CD4, and CD8) and immune exhaustion (forkhead/winged helix transcription factor and programmed cell death-ligand 1) markers in the non-tumor-bearing mucosa were evaluated.

In histologic features, glandular atrophy and intestinal metaplasia in the gastric mucosa significantly improved following H. pylori eradication in the control group (p < 0.001, 0.008), whereas they did not improve in the metachronous group (p = 0.449, 0.609). CD8 and CD8/CD3 ratios increased in the control group (p < 0.001, 0.04), but did not show differences in the metachronous group (p = 0.057, 0.245). The CD4/CD3 ratio and programmed cell death-ligand 1/CD4 expression significantly decreased after H. pylori eradication in the control group (p = 0.003, 0.042), but not in the metachronous group (p = 0.54, 0.55).

This observational study suggests that H. pylori eradication may prevent the recurrence of gastric neoplasia by improving histological inflammation and overcoming immune exhaustion.

Gastric cancer is a prevalent gastrointestinal tumor. In the classical cascade of gastric cancer development, the gradual progression from non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, to intraepithelial neoplasia eventually leads to early gastric cancer. We investigated the proteomic characteristics of chronic gastritis (CG), low-grade intraepithelial neoplasia (low-grade LGIN), and early gastric cancer (EGC). Additionally, we utilized transcriptomic databases to explore the expression patterns of ITGB2 across different stages of gastric tissue and its correlation with the prognosis of gastric cancer. The expression of ITGB2 was confirmed in cytological experiments, revealing that ITGB2 can influence the onset and progression of gastric cancer via the CXCL1-CXCR2 axis. This finding suggests that ITGB2 represents a novel biomarker for gastric cancer, making it a potential target for accurate diagnosis and treatment.

Gastric adenocarcinoma is a highly lethal neoplasm with a short survival especially when metastatic. Few effective treatments are available for the control of the disease and palliation of patients with metastatic gastric cancer. Although progress has been made in the elucidation of molecular pathways invoked in gastric carcinogenesis, this knowledge has not yet led to major breakthroughs, in contrast to several other types of cancer. The role of stem cell transcription factors SOX2 and CDX2 is of particular interest in the pathogenesis of gastric cancer.

The cohort of gastric adenocarcinomas from The Cancer Genome Atlas (TCGA) was interrogated and two groups of gastric cancers, with CDX2 induction and SOX2 suppression on the one hand and with CDX2 induction and SOX2 maintained expression on the other hand were retained. The induction of expression of the two transcription factors was defined as a mRNA expression z score compared with normal samples above zero. The two groups were compared for clinical-pathologic and genomic differences.

Among gastric cancers with up-regulated CDX2 mRNA, cancers with suppressed SOX2 mRNA were slightly more numerous (55.9%) than those with a maintained SOX2 expression. The SOX2 suppressed group had a higher prevalence of MSI high cancers (30.9% versus 10%) and of cases with high tumor mutation burden (35% versus 12.4%) than cancers with a SOX2 maintained expression, which presented more frequently high Chromosomal Instability (CIN). The group with SOX2 suppression had higher rates of mutations in many gastric cancer-associated genes such as epigenetic modifiers ARID1A, KMT2D, KMT2C, and KMT2B, as well as higher rates of mutations in genes encoding for receptor tyrosine kinases ERBB4 and FGFR1. On the other hand, TP53 mutations and amplifications in MYC, ERBB2, and CCNE1 were more common in the group with a maintained expression of SOX2, approaching significance for MYC.

Notable differences are present in the genomic landscape of CDX2-induced gastric cancer depending on the level of expression of SOX2 mRNA. Despite this, SOX2 mRNA expression levels were not prognostic.

This study analyzed the loss of heterozygosity (LOH) effect on gastric cancer (GC) tumor samples from 21 Mexican patients, including diffuse (DGC) and intestinal (IGC) subtypes, as well as non-atrophic gastritis (NAG, control). Whole-genome high-density arrays were performed, and LOH regions were identified among the tissue samples. The differences in affected chromosomes were established among groups, with chromosomes 6 and 8 primarily affected in DGC and chromosomes 3, 16, and 17 in IGC. Functional pathway analysis revealed involvement in cancer-associated processes, such as signal transduction, immune response, and cellular metabolism. Five LOH-genes (IRAK1, IKBKG, PAK3, TKTL1, PRPS1) shared between GC and NAG suggest an early role in carcinogenesis. Specific genes were highlighted for Hallmarks of Cancer NAG-related genes (PTPRJ and NDUFS) were linked to cell proliferation and growth; IGC genes (GNAI2, RHOA, MAPKAPK3, MST1R) to genomic instability, metastasis, and arrest of cell death; and DGC genes to energy metabolism and immune evasion. These findings emphasize the role of LOH in GC pathogenesis and underscore the need for further research to understand LOH-affected genes and their diagnostic or evolution potential in cancer management. Portions of this text were previously published as part of a preprint (https://www.medrxiv.org/content/10.1101/2024.07.29.24311063v1).

Helicobacter pylori (H. pylori) infection is a significant risk factor for gastric cancer (GC) development. A growing body of evidence suggests a causal link between infection with H. pylori and increased DNA breakage in the host cells. While several mechanisms have been proposed for this damage, their relative impact on the overall bacterial genotoxicity is unknown. Moreover, the link between the formation of DNA damage following infection and the emergence of cancerous structural variants (SV) in the genome of infected cells remained unexplored.

We constructed a high-resolution map of genomic H. pylori-induced recurrent break sites using the END-seq method on AGS human gastric cells before and after infection. We next applied END-seq to cycling and arrested cells to identify the role of DNA replication on break formation. Recurrent H. pylori-mediated break sites were further characterized by analyzing published RNA-seq, DRIP-seq, and GRO-seq data at these sites. γH2AX staining and comet assay were used for DNA breakage quantification. Liquid chromatography-mass spectrometry (LC-MS) assay was used to quantify cellular concentrations of dNTPs.

Our data indicated that sites of recurrent H. pylori-mediated DNA breaks are ubiquitous across cell types, localized at replication-related fragile sites, and their breakage is dependent on replication. Consistent with that, we found that H. pylori inflicts nucleotide depletion, and that rescuing the cellular nucleotide pool largely reduced H. pylori-induced DNA breaks. Intriguingly, we found that this genotoxic mechanism operates independently of H. pylori cag pathogenicity island (CagPAI) that encodes for the bacterial type 4 secretion system (T4SS), and its virulence factor, CagA, which was previously implicated in increasing DNA damage by downregulating the DNA damage response. Finally, we show that sites of recurrent H. pylori-mediated breaks coincide with chromosomal deletions observed in patients with intestinal-type GC and that this link potentially elucidates the persistent transcriptional alterations observed in cancer driver genes.

Our findings indicate that dNTP depletion by H. pylori is a key component of its genotoxicity and suggest a link between H. pylori genotoxicity and its oncogenic potential.

Despite a decline in global incidence, gastric cancer (GC) remains a major health concern. The development of GC is a sequential, multistage maladaptive process involving numerous different factors. Understanding the complexity of GC development is crucial for early detection, effective treatment, and, ultimately, prevention. In this respect, identifying the impact of risk factors contributing to the emergence or progression of GC, such as Helicobacter pylori infection, host and bacterial genetics, alcohol consumption, smoking, and preserved foods, will aid in combatting this disease. In this review, we focus on recent developments in understanding the role of the microbiome, dysfunctional molecular pathways, and immune evasion in gastric pathophysiology. We also highlight challenges and advances in treatment of GC.

Chronic atrophic gastritis (CAG) is a global disease of the digestive system and is an important precancerous lesion in the development of gastric cancer. Yang Wei Shu granule (YWSG), which evolved from the formula "Warm Stomach Soup" of the Jin and Yuan Dynasties in China, is frequently used as a classic herbal compound in the treatment of CAG. However, the active ingredients and mechanisms by which it works are not clear.

To elucidate the chemical composition of YWSG and investigate the potential mechanisms of YWSG on CAG by composition analysis, network pharmacology and cellular experimental studies.

The chemical and blood-entry constituents of YWSG were analyzed by ultra-high performance liquid chromatography-Quadrupole tandem time-of-flight mass spectrometry (UPLC-QTOF-MS/MS). Subsequently, potential targets of YWSG for CAG treatment were identified through utilization of publicly available online resources. The YWSG-component-target-pathway network and protein-protein interaction (PPI) network were constructed using Cytoscape software. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of potential targets was performed using the DAVID database. Finally, a cellular model of lipopolysaccharide (LPS)-activated RAW 264.7 macrophages was established and validated by in vitro experiments.

A total of 150 compounds in YWSG and 47 blood-entry constituents were identified by using UPLC-QTOF-MS/MS. Based on network pharmacology, a total of 132 target genes were identified as being involved in the therapeutic effect of YWSG on CAG. Network pharmacology and molecular docking results suggest that AKT1, PIK3CA, PTPN11, SRC and STAT3 may be potential targets of YWSG for the treatment of CAG. Cellular experiments showed that the YWSG-containing serum had no cytotoxic effect on RAW264.7 cells and could inhibit nitric oxide (NO) production and the expression of pro-inflammatory factors TNF-α, IL-6, and IL-1β. Additionally, it was observed to promote the expression of the anti-inflammatory factor IL-10 in LPS-stimulated RAW264.7 cells. The immunofluorescence results showed that YWSG treated CAG by inhibiting the PI3K-Akt pathway.

The application of UPLC-Q-TOF-MS/MS, network pharmacology and cellular experiments provided elucidation to understand the components and mechanisms of the therapeutic effects of YWSG on CAG, providing useful directions for further research.

Gastric carcinoma (GC) is a malignancy with multifactorial involvement, multicellular regulation, and multistage evolution. The classic Correa's cascade of intestinal GC specifies a trilogy of malignant transformation of the gastric mucosa, in which normal gastric mucosa gradually progresses from inactive or chronic active gastritis (Phase I) to gastric precancerous lesions (Phase II) and finally to GC (Phase III). Correa's cascade highlights the evolutionary pattern of GC and the importance of early intervention to prevent malignant transformation of the gastric mucosa. Intervening in early gastric mucosal lesions, i.e., Phase I and II, will be the key strategy to prevent and treat GC. Natural products (NPs) have been an important source for drug development due to abundant sources, tremendous safety, and multiple pharmacodynamic mechanisms. This review is the first to investigate and summarize the multi-step effects and regulatory mechanisms of NPs on the Correa's cascade in gastric carcinogenesis. In phase I, NPs modulate Helicobacter pylori urease activity, motility, adhesion, virulence factors, and drug resistance, thereby inhibiting H. pylori-induced gastric mucosal inflammation and oxidative stress, and facilitating ulcer healing. In Phase II, NPs modulate multiple pathways and mediators regulating gastric mucosal cell cycle, apoptosis, autophagy, and angiogenesis to reverse gastric precancerous lesions. In Phase III, NPs suppress cell proliferation, migration, invasion, angiogenesis, and cancer stem cells, induce apoptosis and autophagy, and enhance chemotherapeutic drug sensitivity for the treatment of GC. In contrast to existing work, we hope to uncover NPs with sequential therapeutic effects on multiple phases of GC development, providing new ideas for gastric cancer prevention, treatment, and drug development.

Chronic atrophic gastritis (CAG), precancerous lesions of gastric cancer (PLGC), and gastric cancer (GC), seriously threaten human health. Traditional Chinese medicine (TCM) has been employed in the treatment of chronic diseases for a long time and has shown remarkable efficacy.

Recently, there has been an increasing use of TCM in treating CAG, PLGC, and GC. The objective of this study is to compile a comprehensive overview of the existing research on the effects and molecular mechanisms of TCM, including formulas, single herbs, and active components.

To obtain a comprehensive understanding of traditional use of TCM in treating these diseases, we reviewed ancient books and Chinese literature. In addition, keywords such as "TCM", "CAG", "PLGC", "GC", and "active ingredients" were used to collect modern research on TCM published in databases such as CNKI, Web of Science, and Pubmed up to April 2024. All collected information was then summarized and analyzed.

This study analyzed 174 articles, which covered the research progress of 20 TCM formulas, 14 single herbs, and 50 active ingredients in treating CAG, PLGC, and GC. Sources, effects, and molecular mechanisms of the TCM were summarized.

This article reviews the progress of TCM in the management of CAG, PLGC, and GC, which will provide a foundation for the clinical application and further development of TCM.

Gastric cancer is a major global health concern, being the final stage of a long-term process, primarily associated with Helicobacter pylori (H. pylori) infection. Early childhood acquisition of H. pylori with low spontaneous eradication rates underscores the need for preventive measures. Our previous pilot treatment study revealed high eradication rates, favourable tolerance profile and a decline in serum biomarkers indicative of gastric damage in asymptomatic school-aged children. The purpose of this study is to determine the potential benefit of a 'screen-and-treat' strategy targeting persistently infected, asymptomatic adolescents. Specific aims are to assess eradication efficacy, its clinical and molecular outcomes and potential clinical and microbiological side effects.

The screening phase will involve testing 500-1000 asymptomatic adolescents aged 14-18 from three cities in Chile using the urea breath test (UBT) to identify 210 participants with persistent infection. They will proceed to a randomised, non-blinded, controlled trial, receiving either a sequential eradication scheme for H. pylori or no treatment. Follow-up will span up to 24 months post-treatment, involving UBT, gastroenterological assessments and blood and stool sample collections. Concurrently, a subset of 60 uninfected adolescents will undergo matched follow-up. Enzyme-linked immunosorbent assay (ELISA) commercial kits will evaluate gastric damage biomarkers in serum (pepsinogen I and II, gastrin-17, VCAM-1, CXCL13). Stool samples will be employed for Escherichia coli and Enterococcus spp-culture, assessing AMR via the disk diffusion method. H. pylori clarithromycin resistance will be determined by molecular method from stool samples. The gut microbiome will be characterised by amplifying and sequencing the 16S rRNA gene from stool samples, followed by bioinformatics analysis.

Approved by the Human Research Ethics Committee at the Faculty of Medicine, University of Chile (073-2022). Findings will be disseminated in peer-reviewed journals and scientific meetings to guide future practices.

NCT05926804.

Helicobacter pylori (H. pylori) plays an important role in the malignant transformation of the gastric mucosa from chronic inflammation to cancer. However, the mechanisms underlying the epigenetic regulation of gastric carcinogenesis mediated by H. pylori remain unclear. Here, we uncover that H. pylori inhibits METTL14 by upregulating ATF3. METTL14 inhibits gastric cancer (GC) cell proliferation and metastasis in vitro and in vivo. Downregulation of METTL14 inhibits Vesicle-associated membrane protein-3 (VAMP3) by reducing the m6A modification level of VAMP3 mRNA and the stability of IGF2BP2-dependent mRNA. H. pylori also accelerates the malignant progression of GC by regulating VAMP3/LC3C-mediated c-Met recycling. Moreover, the expression of METTL14 and VAMP3 in Hp+ chronic gastritis tissues is much lower than that in Hp- chronic gastritis tissues. METTL14 and VAMP3 expression levels are downregulated notably in cancerous tissues of patients with GC. Therefore, our results show a novel METTL14-VAMP3-LC3C-c-Met signalling axis in the GC development mediated by H. pylori infection, which reveals a novel m6A epigenetic modification mechanism for GC and provides potential prognostic biomarkers for GC progression.

Chronic atrophic gastritis (CAG) is a prevalent form of chronic gastritis that presents with chronic inflammation of the gastric mucosa, localised gastric mucosal glandular atrophy and intestinal metaplasia. Despite the existence of diagnostic criteria, effective therapeutic strategies for this condition remain to be developed. The objective of this study was to examine the potential therapeutic benefits of epiberberine in mitigating MNNG-induced CAG and to elucidate the underlying mechanisms. MNNG was employed to establish a CAG mouse model and a GES-1 cell model, and EPI was observed to be efficacious in ameliorating the gastric mucosal injury and inflammatory infiltration induced by MNNG in the CAG model mice, a finding that was subsequently validated in the GES-1 model cells. Bioinformatics analysis indicated that EPI may exert a direct effect on EGFR, thereby regulating the expression of IL-33 and thereby achieving the therapeutic effect of CAG. This hypothesis was also validated by molecular docking prediction, CETSA, and overexpression of EGFR in GES-1 model cells, using EGFR agonists and inhibitors to further demonstrate that EPI may act as an antagonist supplement to EGFR for the treatment of CAG.

Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA-positive H. pylori. Tert knockout significantly ameliorated H. pylori-induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.

The applications of artificial intelligence (AI) and deep learning (DL) are leading to significant advances in cancer research, particularly in analysing histopathology images for prognostic and treatment-predictive insights. However, effective translation of these computational methods requires computational researchers to have at least a basic understanding of histopathology. In this work, we aim to bridge that gap by introducing essential histopathology concepts to support AI developers in their research. We cover the defining features of key cell types, including epithelial, stromal, and immune cells. The concepts of malignancy, precursor lesions, and the tumour microenvironment (TME) are discussed and illustrated. To enhance understanding, we also introduce foundational histopathology techniques, such as conventional staining with hematoxylin and eosin (HE), antibody staining by immunohistochemistry, and including the new multiplexed antibody staining methods. By providing this essential knowledge to the computational community, we aim to accelerate the development of AI algorithms for cancer research.

The early diagnosis and treatment of Gastric Intraepithelial Neoplasia (GIN) are pivotal for improving the survival rates of patients with gastric cancer (GC). Regrettably, reliable noninvasive biomarkers for GIN screening are currently lacking.

mRNA data from the GEO database, pan-cancer data from the TCGA database, and a gene list of exocrine proteins were subjected to integrated analysis to identify a noninvasive biomarker for GIN. The scRNA-seq data analysis, IHC and Elisa were employed to validate the expression of the biomarker in the serum and tissues of clinical patients across different pathological stages.

MUC17 has been identified as a non-invasive diagnostic marker for GIN. It is upregulated in GIN prior to the onset of gastric carcinogenesis and downregulated in other tumors, with high GC specificity. The area under the curve values of serum MUC17 for differentiating chronic gastritis (CG) from low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and early gastric cancer (EGC) were 0.8788, 0.8544, and 0.9513, respectively. Additionally, low plasma MUC17 levels were found to be significantly lower in gastric ulcer (GU), gastric neuroendocrine tumor (GNET), and gastrointestinal stromal tumor (GIST) compared to GIN. The AUC for differentiating between GIN and GU, GNET, or GIST was 0.7803, 0.9244 and 0.9796, respectively.

These findings suggest that plasma MUC17 levels hold substantial promise as a screening biomarker for individuals with GIN and EGC, effectively identifying high-risk groups that necessitate further gastroscopy.

Gastric cancer (GC) incidence remains high worldwide, and the survival rate is poor. GC develops from atrophic gastritis (AG), associated with Helicobacter pylori (Hp) infection, passing through intestinal metaplasia and dysplasia steps. Since Hp eradication does not exclude GC development, further investigations are needed. New data suggest the possible role of unexplored gastric microbiota beyond Hp in the progression from AG to GC. Aimed to develop a score that could be used in clinical practice to stratify GC progression risk, here was investigate gastric microbiota in AG Hp-negative patients with or without high-grade dysplasia (HGD) or GC.

Consecutive patients undergoing upper endoscopy within an endoscopic follow-up for AG were considered. The antrum and corpus biopsies were used to assess the microbiota composition along the disease progression by sequencing the 16S ribosomal RNA gene. Statistical differences between HGD/GC and AG patients were included in a multivariate analysis.

HGD/GC patients had a higher percentage of Bacillus in the antrum and a low abundance of Rhizobiales, Weeksellaceae and Veillonella in the corpus. These data were used to calculate a multiparametric score (Resident Gastric Microbiota Dysbiosis Test, RGM-DT) to predict the risk of progression toward HGD/GC. The performance of RGM-DT in discriminating patients with HGD/GC showed a specificity of 88.9%.

The microbiome-based risk prediction model for GC could clarify the role of gastric microbiota as a cancer risk biomarker to be used in clinical practice. The proposed test might be used to personalize follow-up program thanks to a better cancer risk stratification.

Helicobacter pylori infection causes gastritis, peptic ulcers, and gastric cancer. The infection is typically acquired in childhood and persists throughout life. The major impediment to successful therapy is antibiotic resistance. This systematic review and meta-analysis aimed to comprehensively assess the global prevalence of antibiotic resistance in pediatric H. pylori infection.

We performed a systematic search of publication databases that assessed H. pylori resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, and tetracycline in children. The WHO region classification was used to group pooled primary and secondary resistance estimates along with 95% confidence interval (CI). H. pylori antibiotic resistance rates were retrieved and combined with odds ratios (95% CI) to investigate the global prevalence and temporal trends. Subgroup analysis of the prevalence of antibiotic resistance was conducted by country, age groups, and susceptibility testing methods.

Among 1417 records obtained initially, 152 studies were selected for eligibility assessment after applying exclusion criteria in multiple steps. Ultimately, 63 studies involving 15,953 individuals were included comprising data from 28 countries in 5 WHO regions. The primary resistance rates were metronidazole 35.3% (5482/15,529, 95% CI: 28.7-42.6), clarithromycin 32.6% (5071/15,555, 95% CI: 27.7-37.9), tetracycline 2.1% (148/7033, 95% CI: 1.3-3.6), levofloxacin 13.2% (1091/8271, 95% CI: 9.3-18.4), and amoxicillin 4.8% (495/10305, 95% CI: 2.5-8.8). Raising antibiotic resistance was detected in most WHO regions.

The escalating trend of H. pylori antibiotic resistance in children warrants urgent attention globally. National and regional surveillance networks are required for antibiotic stewardship in children infected with H. pylori.

In recent years, the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) have been considered potential predictors of survival outcomes in various solid tumors, including gastric cancer. However, there is a notable lack of research focusing on their prognostic implications specifically in the early stage of gastric cancer. This study aims to investigate the prognostic indicators of early gastric cancer (EGC), including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), SII, PNI, and lymph node metastasis (LNM).

In this retrospective analysis, we examined 490 patients diagnosed with EGC (pT1Nx). The peripheral blood indices of interest were SII, PNI, PLR, and NLR. The receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to determine optimal cutoff values and prognostic efficacy for each parameter. Additionally, Kaplan-Meier survival curves and multivariate Cox regression models were utilized to delineate independent prognostic factors.

The optimal cutoff values for SII and PNI were determined as 613.05 and 42.21, respectively. Patients in the low SII (SII-L) group demonstrated significantly higher 5-year Disease-Free Survival (DFS) and Overall Survival (OS) rates of 94.7% and 96.2%, compared to the high SII (SII-H) group (DFS: 78.7%; OS: 81.9%), with both differences proving statistically significant (P < 0.001, P < 0.001). Similarly, patients in the high PNI (PNI-H) group showed superior 5-year DFS (93.3%) and OS rates (95.1%) versus the low PNI (PNI-L) group (DFS: 71.4%; OS: 74.3%), also demonstrating statistical significance (P < 0.001, P < 0.001). Multivariate analysis identified SII, PNI, and LNM as independent prognostic factors for EGC. A combined analysis of SII, PNI, and LNM yielded a C-index of 0.723 (P = 0.008).

SII, PNI, and LNM are effective markers for predicting the survival outcomes of patients undergoing radical gastrectomy for EGC.

There has been a paradoxical rise in young-onset gastric cancer (YOGC), defined as gastric cancer (GC) diagnosed before age 50. Precursor lesions may contribute to pathogenesis, though their role in progression to different histologic subtypes is unclear. The impact of self-reported race is also poorly characterized and may be unreliable as a proxy for genetic differences. We aimed to compare differences in histology and genetic ancestry between YOGC and average-onset gastric cancer (AOGC).

This retrospective cohort included all patients with GC at Memorial Sloan Kettering (MSK) from January 2013 to March 2021. Data on demographics, tumor characteristics, and precursor lesions were collected. Genetic ancestry was inferred from MSK-Integrated Mutation Profiling of Actionable Cancer Targets panel.

Of 1685 individuals with GC, 290 had YOGC. Compared to AOGC, individuals with YOGC tended to be female, Hispanic, foreign-born, and feature diffuse-type histology. YOGC was less likely to have precursor lesions, including intestinal metaplasia (20% vs. 37%, p < 0.01) and dysplasia (4% vs. 14%, p < 0.01). Of 560 patients with ancestry data, 127 had YOGC. Admixed, East Asian, and South Asian ancestries were more likely to present with YOGC while Europeans presented with AOGC. Intestinal metaplasia was enriched among East Asians, maintained when stratifying by histology and GC onset.

We observed YOGC was more common in East and South Asians, and while YOGC may be less likely to develop in the setting of precursor lesions these high-risk states may also be enriched in East Asians. Future research is needed to understand drivers behind such differences and outcome disparities given these individuals may be less amenable to endoscopic interventions.

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.

Helicobacter pylori (Hp) is the main trigger of chronic gastric atrophy and the main leading cause of gastric cancer. Hp infects the normal gastric mucosa and can lead to chronic inflammation, glandular atrophy, intestinal metaplasia, dysplasia and finally adenocarcinoma. Chronic inflammation and gastric atrophy associated with Hp infection appear initially in the distal part of the stomach (the antrum) before progressing to the proximal part (the corpus-fundus). In recent years, endoscopic developments have allowed for the characterization of various gastric conditions including the normal mucosa (pyloric/fundic gland pattern and regular arrangement of collecting venules), Hp-related gastritis (Kyoto classification), glandular atrophy (Kimura-Takemoto classification), intestinal metaplasia (Endoscopic Grading of Gastric Intestinal Metaplasia), and dysplasia/adenocarcinoma (Vessel plus Surface classification). Despite being independent classifications, all these scales can be integrated into a single model: the endoscopic model for gastric carcinogenesis. This model would assist endoscopists in comprehending the process of gastric carcinogenesis and conducting a systematic examination during gastroscopy. Having this model in mind would enable endoscopists to promptly recognize the implications of Hp infection and the potential patient's risk of developing gastric cancer.

Epigenetic modifications are crucial in tumourigenesis, yet the changes in novel epigenetic regulators like 5-hydroxymethylcytosines (5hmC) during the evolution of gastric premalignant lesions remain poorly understood. This study aims to investigate the implications of 5hmC in the progression from gastric premalignant lesions to gastric adenocarcinoma (GAC).

To our knowledge, we conducted the largest and longest longitudinal study of a Chinese population with gastric precursor lesions, involving 29,176 patients with gastritis who underwent gastroscopy and biopsy between 2001 and 2015, with follow-up until 1 August, 2022. The median follow-up time was 12.2 years, and the overall GAC incidence rate was 0.82%. Genome-wide mapping of 5hmC in gastric premalignant lesions from a subset of individuals was performed using the 5hmC-Seal assay, including 21 samples that progressed to GAC during follow-up and 48 non-progressed age- and sex-matched controls.

We identified 213 differentially modified gene bodies, primarily concentrated in pathways related to cell division, cell cycle, energy metabolism, inflammation and tumourigenesis. An exploratory study was conducted to summarize a 5hmC-based epigenetic model for predicting cancer progression using multivariable logistic regression and machine learning. The nine-gene model showed an area under the curve of 87.5% (95% confidence interval: 72%-100%) in the validation samples (one of three), which were set aside before model training.

This study is the first to explore the 5hmC molecular landscape in gastric premalignant lesions, suggesting relevant pathways implicated in their evolution to GAC as well as the feasibility of exploiting genome-wide 5hmC mapping in assessing the risk of future cancer progression.

A largest longitudinal follow-up study of gastric precursor lesions in Chinese patients. Revealing novel 5hmC molecular landscape linked to gastric premalignant lesions. The feasibility of an innovative 5hmC-based predictive model for assessing gastric cancer progression risk.

The human microbiome is the complex ecosystem consisting of trillions of microorganisms that play a key role in developing the immune system and nutrient metabolism. Alterations in the gut microbiome have been linked to cancer initiation, progression, metastasis, and response to treatment. Accumulating evidence suggests that levels of vitamins and minerals influence the gut environment and may have implications for cancer risk and progression. Bifidobacterium has been reported to reduce the colorectal cancer risk by binding to free iron. Additionally, zinc ions have been shown to activate the immune cells and enhance the effectiveness of immunotherapy. Higher selenium levels have been associated with a reduced risk of several cancers, including colorectal cancer. In contrast, enhanced copper uptake has been implicated in promoting cancer progression, including colon cancer. The interaction between cancer and gut bacteria, as well as dysbiosis impact has been studied in animal models. The interplay between prebiotics, probiotics, synbiotics, postbiotics and gut bacteria in cancer offers the diverse physiological benefits. We also explored the particular probiotic formulations like VSL#3, Prohep, Lactobacillus rhamnosus GG (LGG), etc., for their ability to modulate immune responses and reduce tumor burden in preclinical models. Targeting the gut microbiome through antibiotics, bacteriophage, microbiome transplantation-based therapies will offer a new perspective in cancer research. Hence, to understand this interplay, we outline the importance of micronutrients with an emphasis on the immunomodulatory function of the microbiome and highlight the microbiome's potential as a target for precision medicine in cancer treatment.

Helicobacter pylori (H. pylori) is closely associated with gastric cancer and peptic ulcers. The effectiveness of antibiotic treatment against H. pylori is diminished by the emergence of drug-resistant strains, side effects, high cost and reinfections. Given the circumstances, it is imperative to develop a potent vaccination targeting H. pylori. Understanding H. pylori's pathogenicity and the host's immune response is essential to developing a vaccine. Furthermore, vaccine evaluation necessitates the careful selection of design formulation. This review article aims to provide a concise overview of the considerations involved in selecting the optimal antigen, adjuvant, vaccine delivery system and laboratory animal model for vaccine formulation. Furthermore, we will discuss some significant obstacles in the realm of developing a potent vaccination against H. pylori.

Gastric cancer (GC) is one of the most common malignancies and a prominent cause of cancer mortality worldwide. A distinctive characteristic of GC is its intimate association with commensal microbial community. Although Helicobacter pylori is widely recognised as an inciting factor of the onset of gastric carcinogenesis, increasing evidence has indicated the substantial involvement of microbes that reside in the gastric mucosa during disease progression. In particular, dysregulation in gastric microbiota could play pivotal roles throughout the whole carcinogenic processes, from the development of precancerous lesions to gastric malignancy. Here, current understanding of the gastric microbiota in GC development is summarised. Potential translational and clinical implications of using gastric microbes for GC diagnosis, prognosis and therapeutics are also evaluated, with further discussion on conceptual haziness and limitations at present. Finally, we highlight that modulating microbes is a novel and promising frontier for the prevention and management of GC, which necessitates future in-depth investigations.

Detection of gastric cancer (GC) at early stages is an effective strategy for decreasing mortality. This study aimed to construct a prediction nomogram based on a questionnaire to assess the risk of developing GC.

Our study comprised a total of 4379 participants (2326 participants from outpatient at Fengqing People's Hospital were considered for model development and internal validation, and 2053 participants from outpatients at the endoscopy center at the Seventh Affiliated Hospital of Sun Yat-Sen University were considered for independent external validation) and gastric mucosa status was determined by endoscopy and biopsies. The eligible participants in development cohort from Fengqing people's Hospital were randomly separated into a training cohort (n=1629, 70.0%) and an internal validation cohort (n=697, 30.0%). The relevant features were selected by a least absolute shrinkage and selection operator (LASSO), and the ensuing features were evaluated through multivariable logistic regression analysis. Subsequently, the variables were selected to construct a prediction nomogram. The discriminative ability and predictive accuracy of the nomogram were evaluated by the C-index and calibration plot, respectively. Decision curve analysis (DCA) curves were used for the assessment of clinical benefit of the model. This model was developed to estimate the risk of developing neoplastic lesions according to the "transparent reporting of a multivariable prediction model for individual prognosis or diagnosis" (TRIPOD) statement.

Six variables, including age, sex, alcohol consumption, cigarette smoking, education level, and Hp infection status, were independent risk factors for the development of neoplastic lesions. Thus, these variables were incorporated into the final nomogram. The AUC of the nomogram were 0.701, 0.657 and 0.699 in the training, internal validation, and external validation cohorts, respectively. The calibration curve showed that the nomogram was in good agreement with the observed outcomes. Compared to treatment of all patients or none, our nomogram showed a notably higher clinical benefit.

This nomogram proved to be a convenient, cost-effective tool to effectively predict an individual's risk of developing neoplastic lesions, and it can act as a prescreening tool before gastroscopy.

Current gastric cancer (GC) screening modalities are invasive and expensive. Noninvasive screening for GC precursors with serum pepsinogen (PG) may improve early detection and prevention. Test characteristics of PG based on US prospective data was recently reported and used to study the cost-effectiveness of PG screening vs no screening in the US.

A patient-level state transition microsimulation of gastric adenocarcinoma analyzed noninvasive screening vs no screening in a hypothetical cohort of average risk US individuals. Primary outcomes included life expectancy, quality-adjusted life years, total costs, and incremental cost-effectiveness ratios. Secondary outcomes included total GC incidence and mortality. Base-case PG sensitivity and specificity were 34.1% and 94.7%, respectively, with a wide range of PG performance characteristics also examined.

One-time serum PG screening at age 40 was cost-effective compared to no screening with an incremental cost-effectiveness ratio of $4913.29 per quality-adjusted life year. PG screening resulted in 10.9% relative reduction in lifetime GC incidence and 10.8% relative decrease in cumulative GC mortality. Localized stage at diagnosis increased from 30.5% to 33.6% and metastatic stage decreased from 40.8% to 37.4%. Sensitivity analysis showed PG screening was most sensitive to endoscopy costs, chronic atrophic gastritis quality of life, and PG prevalence. PG screening remained cost-effective across a wide range of test values.

PG screening is a cost-effective strategy to improve GC mortality; however, mortality benefit will depend on the test characteristics of the biomarker. Future blood-based screening tests that have better performance characteristics could further improve GC prevention.

Precancerous lesions typically precede gastric cancer (GC), but the molecular mechanisms underlying the transition from these lesions to GC remain unclear. Therefore, it is urgent to understand this transition from precancerous lesions to GC, which is crucial for the early diagnosis and treatment of GC. In this study, we merged multiple single-cell RNA sequencing datasets to investigate the molecular changes in distinct cell types associated with the progression of GC. First, we observed an increasing abundance of immune cells and a decrease in non-immune cells from non-atrophic gastritis to GC. Five immune cell types were significantly enriched in GC compared to precancerous lesions. Moreover, we found that the interleukin (IL)-17 signaling pathway and Th17 cell differentiation were significantly up-regulated in immune cell subsets during GC progression. Some genes in these processes were predominantly expressed at the GC stage, highlighting their potential as diagnostic markers. Furthermore, we validated our findings using bulk RNA sequencing data from The Cancer Genome Atlas and confirmed consistent immune cell changes during GC progression. Our study provides insights into the immune infiltration and signaling pathways involved in the development of GC, contributing to the development of early diagnosis and targeted treatment strategies for this malignancy.