BACKGROUND: Currently, immune checkpoint inhibitors (ICIs) have excellent performance in the clinical treatment of advanced gastric cancer (AGC). However, precisely selecting AGC patients who can benefit from immunotherapy is an urgent difficulty. In this study, we investigated the immunoprognostic role of myeloid-to-lymphocyte ratio (M:L) in AGC patients.
METHODS: We collected information on 268 AGC patients who were hospitalized in the Department of Medical Oncology of PLA General Hospital from December 2014 to May 2021. The patients were divided into low M: L group (< 3.76) and high M:L group (≥ 3.76). Survival differences between different M: L level groups at baseline and after treatment were analyzed by methods such as Kaplan-Meier, Cox or Logistic regression model.
RESULTS: Progression free survival (PFS) (5.8 months vs. 3.4 months, p = 0.001) and overall survival (OS) (14.1 months vs. 9.0 months, p = 0.001) were significantly longer in the low M:L group than in the high M:L group. After analyses of Cox regression modeling it was concluded that M:L was an independent prognostic factor for PFS (HR 1.371 95%CI 1.057-1.777 p = 0.017) and OS (HR 1.352 95%CI 1.003-1.824 p = 0.048), respectively. Subsequent subgroup analyses performed across immunotherapy lines, regimens, PD-1 inhibitor agents, and age groups revealed a poorer prognosis in the high M:L group. Notably, an increase in the value of M:L after treatment significantly increased the risk of poor prognosis.
CONCLUSIONS: M:L ≥ 3.76 is associated with poor prognostic outcomes in AGC patients receiving immunotherapy and may be a predictive biomarker of prognosis. This result needs to be confirmed by larger prospective studies.

Helicobacter pylori infection has been linked to gastrointestinal diseases including gastric cancer. High rates of H. pylori infection and gastric cancer have been reported in indigenous populations within the United States. We report whole-genome sequencing of three H. pylori isolates originating from Native American patients presenting with gastric disease.

BACKGROUND: Helicobacter pylori screening with eradication reduces gastric cancer (GC) development. However, it was unknown at what age the H. pylori screening should be implemented to achieve the greatest benefits at the least cost. This study aimed to determine the optimal age of H. pylori screening for primary GC prevention.
METHODS: A state transition model for a hypothetical cohort of 15-year-olds from a healthcare payer perspective on a lifetime horizon was developed. Nine ages for H. pylori testing were considered: 15, 18, 20, 30, 40, 50, 60, 70, and 80 years. H. pylori screening was compared with no screening and annual, biennial, and triennial endoscopies starting at age 50. The main outcomes were costs, quality-adjusted life-years (QALYs), life expectancy life-years (LYs), incremental cost-effectiveness ratios, GC cases, stage I GC cases, and GC-related deaths. One-way, two-way, and probabilistic sensitivity analyses were performed to assess the uncertainty of the parameters.
RESULTS: All H. pylori screenings at ages 15-80 were more cost-effective than all endoscopies and no screening. H. pylori screening at age 15 yielded the greatest cost-saving and benefits. The cost-effectiveness was sensitive to the adherence rate of H. pylori screening at age 15. Cost-effectiveness acceptability curves showed that H. pylori screening at age 15 was 99.6% cost-effective at a willingness-to-pay threshold of US$50,000 per QALY gained. Compared with no screening and biennial endoscopy in 15.6 million 15-year-olds from 2022 to 2037, respectively, H. pylori screening at age 15 saves US$9.70 million and US$2.39 billion, increases 1.26 million QALYs with 1312 LYs and 651 LYs, prevents 436 GC cases with 254 stage I GC cases and 305 stage I GC cases, and avoids 176 GC-related deaths and 72 GC-related deaths.
CONCLUSIONS: The optimal age for population-based H. pylori screening at ages 15-80 is the youngest, 15 years old. Shifting population-based H. pylori screening to younger people will reduce GC morbidity and mortality worldwide, along with a detailed investigation of the feasibility and long-term consequences of H. pylori eradication at a young age.

BACKGROUND: Gastric cancer (GC) is a prevalent malignancy with limited therapeutic options for advanced stages. This study aimed to identify novel therapeutic targets for GC by profiling HSP90 client kinases.
METHODS: We used mass spectrometry-based activity-based protein profiling (ABPP) with a desthiobiotin-ATP probe, combined with sensitivity analysis of HSP90 inhibitors, to profile kinases in a panel of GC cell lines. We identified kinases regulated by HSP90 in inhibitor-sensitive cells and investigated the impact of MASTL knockdown on GC cell behavior. Global proteomic analysis following MASTL knockdown was performed, and bioinformatics tools were used to analyze the resulting data.
RESULTS: Four kinases-MASTL, STK11, CHEK1, and MET-were identified as HSP90-regulated in HSP90 inhibitor-sensitive cells. Among these, microtubule-associated serine/threonine kinase-like (MASTL) was upregulated in GC and associated with poor prognosis. MASTL knockdown decreased migration, invasion, and proliferation of GC cells. Global proteomic profiling following MASTL knockdown revealed NEDD4-1 as a potential downstream mediator of MASTL in GC progression. NEDD4-1 was also upregulated in GC and associated with poor prognosis. Similar to MASTL inhibition, NEDD4-1 knockdown suppressed migration, invasion, and proliferation of GC cells.
CONCLUSIONS: Our multi-proteomic analyses suggest that targeting MASTL could be a promising therapy for advanced gastric cancer, potentially through the reduction of tumor-promoting proteins including NEDD4-1. This study enhances our understanding of kinase signaling pathways in GC and provides new insights for potential treatment strategies.

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BACKGROUND: Cell adhesion molecules (CAMs) play a vital role in cell-cell interactions, immune response modulation, and tumor cell migration. However, the unique role of CAMs in gastric cancer (GC) remains largely unexplored.
METHODS: This study characterized the genetic alterations and mRNA expression of CAMs. The role of CD34, a representative molecule, was validated in 375 GC tissues. The activity of the CAM pathway was further tested using single-cell and bulk characterization. Next, data from 839 patients with GC from three cohorts was analyzed using univariate Cox and random survival forest methods to develop and validate a CAM-related prognostic model.
RESULTS: Most CAM-related genes exhibited multi-omics alterations and were associated with clinical outcomes. There was a strong correlation between increased CD34 expression and advanced clinical staging (P = 0.026), extensive vascular infiltration (P = 0.003), and unfavorable prognosis (Log-rank P = 0.022). CD34 expression was also found to be associated with postoperative chemotherapy and tumor immunotherapy response. Furthermore, the CAM pathway was significantly activated and mediated poor prognosis. Additionally, eight prognostic signature genes (PSGs) were identified in the training cohort. There was a substantial upregulation of the expression of immune checkpoints and a pronounced infiltration of immune cells in GC tissues with high PSG score, which is consistent with the prediction of increased sensitivity to immunotherapy. Moreover, 9 compounds from the CTRPv2 database and 13 from the Profiling Relative Inhibition Simultaneously in Mixture (PRISM) database were identified as potential therapeutic drugs for patients with GC with high PSG score.
CONCLUSIONS: Thorough understanding of CAM pathways regulation and the innovative PSG score model hold significant implications for medical diagnosis, potentially enhancing personalized treatment strategies and improving patient outcomes in GC management.

Gastric cancer is a remarkably heterogeneous tumor. Despite some advances in the diagnosis and treatment of gastric cancer in recent years, the precise treatment and curative outcomes remain unsatisfactory. Poor prognosis continues to pose a major challenge in gastric cancer. Therefore, it is imperative to identify effective targets to improve the treatment and prognosis of gastric cancer patients. It should be noted that glycosylation, a novel form of posttranslational modification, is a process capable of regulating protein function and influencing cellular activities. Currently, numerous studies have shown that glycosylation plays vital roles in the occurrence and progression of gastric cancer. As crucial enzymes that regulate glycan synthesis in glycosylation processes, glycosyltransferases are potential targets for treating GC. Hence, investigating the regulation of glycosyltransferases and the expression of associated proteins in gastric cancer cells is highly important. In this review, the related glycosyltransferases and their related signaling pathways in gastric cancer, as well as the existing inhibitors of glycosyltransferases, provide more possibilities for targeted therapies for gastric cancer.

BACKGROUND: Gastric cancer (GC), as a highly lethal malignancy, is the fourth most common malignancy and the second leading cause of cancer-related death worldwide. This study is an umbrella review of systematic reviews and meta-analyses to present an overview of the extent and reliability of the claimed association between physical activity and the likelihood of developing or dying from GC.
METHODS: This study was conducted following the Joanna Brigs Institute (JBI)\'s methods for conducting umbrella reviews. A systematic search was performed in PubMed, Scopus, Web of Science, and ProQuest databases until July, 2024 with predefined keywords. Two independent authors assessed the Risk of Bias in included studies using the JBI critical appraisal tool for the assessment of the quality of systematic reviews and disagreements between the authors were resolved through discussion or the opinion of another author.
RESULTS: Five systematic reviews were included in this analysis, offering a more comprehensive understanding of the inverse relationship between physical activity and gastric cancer risk. Compared to previous studies, this review provides stronger evidence that moderate-to-high levels of physical activity significantly reduce the overall risk of developing gastric cancer.
CONCLUSIONS: While a link between physical activity and reduced cancer risk is promising, further research is crucial to unravel the specific mechanisms at play and to quantify the impact of increased activity levels on cancer prevention. Based on the findings of this study, physical activity is found to be associated with a decreased risk of GC; however, the limitation of the evidence suggested a need for future studies on this topic.

BACKGROUND: Organoids are approved by the US FDA as an alternative to animal experiments to guide drug development and for sensitivity screening. Stable organoids models of gastric cancer are desirable for personalized medicine and drug screening.
METHODS: Tumor tissues from a primary cancer of the stomach and metastatic cancer of the lymph node were collected for 3D culture. By long-term culture for over 50 generations in vitro, we obtained stably growing organoid lines. We analyzed short tandem repeats (STRs) and karyotypes of cancer cells, and tumorigenesis of the organoids in nude mice, as well as multi-omics profiles of the organoids. A CCK8 method was used to determine the drugs sensitivity to fluorouracil (5-Fu), platinum and paclitaxel.
RESULTS: Paired organoid lines from primary cancer (SPDO1P) and metastatic lymph node (SPDO1LM) were established with unique STRs and karyotypes. The organoid lines resulted in tumorigenesis in vivo and had clear genetic profiles. Compared to SPDO1P from primary cancer, upregulated genes of SPDO1LM from the metastatic lymph node were enriched in pathways of epithelial-mesenchymal transition and angiogenesis with stronger abilities of cell migration, invasion, and pro-angiogenesis. Based on drug sensitivity analysis, the SOX regimen (5-Fu plus oxaliplatin) was used for chemotherapy with an optimal clinical outcome.
CONCLUSIONS: The organoid lines recapitulate the drug sensitivity of the parental tissues. The paired organoid lines present a step-change toward living biobanks for further translational usage.

BACKGROUND: Gastric cancer (GC) stands out as one of the most prevalent malignancies affecting the digestive system, characterized by a substantial incidence rate and mortality. Maternal embryonic leucine zipper kinase (MELK) has been implicated in the advancement of various cancer types and the modulation of the tumor microenvironment. This study aims to delve into the involvement of MELK in chemoresistance and the tumor microenvironment of GC.
METHODS: The MELK expression was detected using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry. Lentiviral transfection was employed to establish stable cell lines with either overexpressed or silenced MELK. The impact of MELK on the chemoresistance of GC cells and the polarization of macrophages was investigated through in vitro and in vivo functional assays. Additionally, the correlation between MELK and the cytokines colony-stimulating factor 1 (CSF-1), as well as stromal macrophages, was analysed. The prognostic significance of MELK, CSF-1, and CD206 expression levels in clinical samples was further investigated.
RESULTS: MELK was found to be highly expressed in chemoresistant GC cells and tissues. Furthermore, both in vitro and in vivo assays indicated that MELK overexpression conferred chemoresistance in GC cells. Additionally, MELK overexpression was observed to induce M2 macrophage polarization via the CSF-1/JAK2/STAT3 pathway, thereby contributing to chemoresistance within the tumor microenvironment. The expression of MELK in GC tissues from neoadjuvant chemotherapy patients correlated positively with CSF-1 and CD206. Moreover, patients with higher expression levels of MELK, CSF-1, or CD206 exhibited significantly shorter OS and DFS rates.
CONCLUSIONS: Our investigation underscores the critical role of MELK in promoting chemoresistance and inducing M2 macrophage polarization in GC. It proposes novel targets and methods for the treatment of GC, as well as prognostic factors for neoadjuvant chemotherapy.