Gastric cancer (GC) is a globally prevalent malignancy with a particularly heavy burden in China. Helicobacter pylori ( H. pylori ) is a Group I carcinogen for GC, with a higher seroprevalence rate indicating a higher GC incidence. However, only approximately 3% of the individuals with H. pylori infection eventually develop GC, and about 2.6% still progress to GC even 10-20 years after the eradication of H. pylori . Thus, the pathogenic mechanism of H. pylori for GC must be elucidated, and high-risk individuals precisely identified. Furthermore, GC can occur even in individuals who have never been infected with H. pylori . As H. pylori infection rates decline, the proportion of H. pylori -negative GC cases is increasing annually, gaining significant research attention. In this review, potential pathogenic mechanisms of H. pylori infection are explored from the aspects of H. pylori virulence factors and host factors (genetic susceptibility and immune microenvironment). Possible risk factors for H. pylori -negative GC include infections by other microorganisms (e.g., bacteria, fungi, and viruses), autoimmune gastritis, bile reflux, genetic mutations, and environmental factors. We aim to review the potential mechanisms for GC with varying H. pylori infection statuses, identify the high-risk individuals, and pose questions that need to be addressed. In the future, as the prevalence of H. pylori infection gradually decreases, GC prevention and management must evolve to address host-specific factors and the growing challenge of H. pylori -negative GC by integrating multidisciplinary perspectives.
Stomach Neoplasms/genetics* ; Humans ; Helicobacter Infections/complications* ; Helicobacter pylori/pathogenicity* ; Risk Factors

OBJECTIVE: To explore the changes of CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) and programmed death-ligand 1 (PD-L1) expression in gastric mucosal epithelial cells after Helicobacter pylori infection and the regulation of CMTM6 on PD-L1, and to analyze the mRNA expression differences before and after CMTM6 gene knock-out in helicobacter pylori infected gastric epithelial cells by microarray analysis. METHODS: The standard Helicobacter pylori strain ATCC 26695 was co-cultured with human gastric epithelial cell GES-1 for 6, 24 and 48 hours, and the mRNA and protein levels of CMTM6 and PD-L1 were detected by real-time quantitative PCR and Western blot. Using CRISPR/Cas9 to construct CMTM6 gene knockout plasmid and knockout CMTM6 gene of GES-1 cells. Helicobacter pylori was co-cultured with CMTM6 gene knockout and wild type GES-1 cells for 48 hours to detect PD-L1 transcription and protein level changes, and CMTM6 gene knockout GES-1 cells were treated with the proteasome inhibitor MG-132 to detect the changes in PD-L1 protein levels. Agilent Human ceRNA Microarray 2019 was used to detect the differentially expressed genes in CMTM6 gene knockout and wild-type GES-1 cells co-cultured with Hp for 48 hours, and the signal pathway of differentially expressed genes enrichment was analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: The mRNA and protein levels of CMTM6 and PD-L1 in GES-1 cells were significantly up-regulated after Helicobacter pylori infection, and CMTM6 mRNA was most significantly up-regulated 48 hours after infection. After CMTM6 gene knockout, the CD274 gene transcription level of Helicobacter pylori infected GES-1 cells did not change significantly, but PD-L1 protein level was significantly down-regulated, and the PD-L1 level increased after the application of proteasome inhibitor MG-132. After CMTM6 gene knockout, 67 genes had more than two times of differential expression. The transcription levels of TMEM68, FERMT3, GPR142, ATP6V1FNB, NOV, UBE2S and other genes were significantly down-regulated. The transcription levels of PCDHGA6, CAMKMT, PDIA2, NTRK3, SPOCK1 and other genes were significantly up-regulated. After CMTM6 gene knockout, ubiquitin-conjugating enzyme E2S (UBE2S) gene expression was significantly down-regulated, which might affect protein ubiquitination degradation. After CMTM6 gene knockout, adrenoceptor alpha 1B (ADRA1B), cholinergic receptor muscarinic 1 (M1), CHRM1, platelet activating factor receptor (PTAFR) gene expression was significantly up-regulated. CONCLUSION Helicobacter pylori infection up-regulates the expression level of CMTM6 in gastric mucosa cells, and CMTM6 can stabilize PD-L1 and maintain the protein level of PD-L1. CMTM6 gene knockout may affect biological behaviors such as protein ubiquitination and cell surface receptor expression.
Humans ; MARVEL Domain-Containing Proteins/metabolism* ; Helicobacter pylori/physiology* ; B7-H1 Antigen/genetics* ; Helicobacter Infections/metabolism* ; Epithelial Cells/metabolism* ; Gastric Mucosa/metabolism* ; Chemokines/metabolism* ; Cell Line ; Gene Knockout Techniques ; Myelin Proteins

Sonodynamic therapy (SDT) can potentially induce immunogenic cell death in tumor cells, leading to the release of ATP, and facilitating the initiation of an immune response. Nevertheless, the enzymes CD39 and CD73 can swiftly convert ATP into immunosuppressive adenosine (ADO), resulting in an immunosuppressive tumor microenvironment (TME). This study introduced a nanomedicine (QD/POM1@NP@M) engineered to reprogram TME by modulating the CD39/CD73/ADO pathway. The nanomedicine encapsulated sonosensitizers silver sulfide quantum dots, and the CD39 inhibitor POM1, while also incorporating homologous tumor cell membranes to enhance targeting capabilities. This integrated approach, on the one hand, stimulates the release of ATP via SDT, thereby initiating the immune response. In addition, it reduced the accumulation of ADO by inhibiting CD39 activity, which ameliorated the immunosuppressive TME. Upon administration, the nanomedicine demonstrated substantial anti-tumor efficacy by facilitating the infiltration of anti-tumor immune cells, while reducing the immunosuppressive cells. This modulation effectively transformed the TME from an immunologically "cold" state to a "hot" state. Furthermore, combined with the checkpoint inhibitor α-PDL1, the nanomedicine augmented systemic anti-tumor immunity and promoted the establishment of long-term immune memory. This study provides an innovative strategy for combining non-invasive SDT and ATP-driven immunotherapy, offering new ideas for future cancer treatment.

Purpose To analyze and discuss the clinicopathological,molecular pathological characteristics,as well as diagnostic and prognostic features of pleomorphic xanthoastrocytoma(PXA)according to the new WHO classifi-cation.Methods 79 cases of PXA were collected to analyze their pathological and clinical data.Immunohistochemis-try using the EnVision method was employed to detect the expression of CD34,ATRX,Rb,Olig-2,H3K27M,H3K27me3,IDH1 R132H,BRAF VE1 and Ki67.Sanger sequencing was used to detect mutations in H3F3A and IDH1/2.Fluorescence quantitative PCR was used to detect the BRAF V600E mutation and TERT promoter region al-terations.Fluorescence in situ hybridization(FISH)was used to detect CDKN2A and EGFR alterations.The relation-ship between clinical,pathological,molecular genetics data,and prognosis was analyzed.Results The patients'ages ranged from 9 to 69 years,with an average age of 36.4 years.Most tumors were located in the temporal lobe,frontal lobe and parietal lobe.Among the 79 cases,42 were classified as grade 2 PXA and 37 as grade 3 PXA.The tumor cells exhibited pleomorphic changes,with perivascular lymphocytic sheaths and eosinophilic bodies frequently ob-served.Grade 3 PXA exhibited more mitotic figures(average of 11.8/10 HPF),and was usually accompanied by nec-rosis,focal marginal infiltration and microvascular proliferation.Immunohistochemistry and molecular characteristics revealed frequent positivity for CD34,BRAF V600E mutation(68.1％),and CDKN2A homozygous deletion(36.8％)in PXA.Some cases showed TERT gene mutation and absent Rb expression.Univariate survival analysis in-dicated that necrosis,focal marginal infiltration,and CNS WHO grade were related to overall survival,while focal infil-tration and CNS WHO grade were the independent risk factors.Conclusion The prognosis of CNS WHO grade 3 PXA is wrose than that of grade 2 PXA.Accurate diagnosis of PXA requires the combination of the morphological features,immunohistochemical staining,and multiple molecular tests.

Objective To investigate the effects of miR-338-3p on interleukin(IL)-13-induced human bronchial epithelial cell line(BEAS-2B)injury and airway inflammation in mice with ovalbumin(OVA)-induced asthma.Methods OVA was used to replicate an asthma model of mice,which were divided into control group,model group,miR-NC agomir and miR-338-3p agomir intervention groups.HE staining microscopy was employed to ob-serve the pathological morphology of lung tissue,while TUNEL staining was used to assess cell apoptosis in lung tis-sue.ELISA was conducted to measure the levels of interleukin-1β(IL-1β)and tumor necrosis factor(TNF)-α in lung tissue.The BEAS-2B cells were subjected to IL-13-induced injury and divided into control group,IL-13 group,IL-13+miR-NC group,and IL-13+miR-338-3p mimic group.Cell viability was assessed with MTT assay.Flow cytometry was employed to evaluate cell apoptosis.The level of IL-1β and TNF-α in cells was measured by ELISA.The targeting relationship between miR-338-3p and Ras homologous(Rho)was investigated using bioinfor-matics analysis,luciferase assay,Western blot,and functional repair assay.Results Compared to the model group,the miR-338-3p agamid intervention group exhibited a significant reduction in inflammatory cell infiltration and airway wall thickening in lung tissue,as well as decreased cell apoptosis and the level of IL-1β and TNF-α in lung tissue(P＜0.05).Compared to the control group,cell viability of BEAS-2B cells in the IL-13+miR-338-3p mimic group exhibited a significant increase(P＜0.05),while apoptosis and level of IL-1β and TNF-α within the cells demonstrated a notable decrease(P＜0.05).Rho was a target gene of miR-338-3p,and over-expression of Rho attenuated the effect of miR-338-3p mimic on IL-13-induced injury and inflammation in BEAS-2B cells.Conclusions Up-regulation of miR-338-3p can inhibit asthma-related airway inflammation and injury of lung epi-thelial cells with a potential mechanism targeting at Rho gene.

A 36-year-old male developed unconsciousness and no response to voice stimuli after taking approximately 2 050 mg felodipine (the specific time was unknown). Two hours later, he was sent to the department of emergency by his family and admitted to the hospital. His vital signs showed body temperature 35.1 ℃, pulse 148 times/min, respiration 32 times/min, and blood pressure 65/34 mmHg. Acute drug poisoning, acute toxic cardiomyopathy, acute toxic shock, acute type Ⅱ respiratory failure, acute toxic encephalopathy, and acute renal failure were diagnosed based on the patient′s clinical manifestations combined with laboratory tests results, cardiac ultrasound, chest and abdominal CT scans. Endotracheal intubation connected to a ventilator for invasive assisted ventilation, pressure boosting, and fluid resuscitation were given. At the same time, repeated gastric lavage and enema were performed to remove toxins. Blood perfusion was intermittently and repeatedly administered, and continuous renal replacement therapy was used. The blood concentration of felodipine was 1 298 μg/L at 2 hours after admission, and cardiac arrest occurred at 4 hours. Venous-arterial extracorporeal membrane oxygenation (V-A ECMO) treatment was administered immediately. After 48 hours of ECMO operation, sedatives were discontinued and the patient′s consciousness was improved after 4 hours. On the 5th day of ECMO treatment, his heart rate was 72 beats per minute, and blood pressure was 127/65 mmHg. The blood concentration of felodipine decreased to 2 μg/L. The patient′s vital signs were significantly improved and ECMO supportive treatment was withdrawn. After 26 days of hospitalization, the patient recovered and was discharged.

Purpose To analyze and discuss the clinicopathological,molecular pathological characteristics,as well as diagnostic and prognostic features of pleomorphic xanthoastrocytoma(PXA)according to the new WHO classifi-cation.Methods 79 cases of PXA were collected to analyze their pathological and clinical data.Immunohistochemis-try using the EnVision method was employed to detect the expression of CD34,ATRX,Rb,Olig-2,H3K27M,H3K27me3,IDH1 R132H,BRAF VE1 and Ki67.Sanger sequencing was used to detect mutations in H3F3A and IDH1/2.Fluorescence quantitative PCR was used to detect the BRAF V600E mutation and TERT promoter region al-terations.Fluorescence in situ hybridization(FISH)was used to detect CDKN2A and EGFR alterations.The relation-ship between clinical,pathological,molecular genetics data,and prognosis was analyzed.Results The patients'ages ranged from 9 to 69 years,with an average age of 36.4 years.Most tumors were located in the temporal lobe,frontal lobe and parietal lobe.Among the 79 cases,42 were classified as grade 2 PXA and 37 as grade 3 PXA.The tumor cells exhibited pleomorphic changes,with perivascular lymphocytic sheaths and eosinophilic bodies frequently ob-served.Grade 3 PXA exhibited more mitotic figures(average of 11.8/10 HPF),and was usually accompanied by nec-rosis,focal marginal infiltration and microvascular proliferation.Immunohistochemistry and molecular characteristics revealed frequent positivity for CD34,BRAF V600E mutation(68.1％),and CDKN2A homozygous deletion(36.8％)in PXA.Some cases showed TERT gene mutation and absent Rb expression.Univariate survival analysis in-dicated that necrosis,focal marginal infiltration,and CNS WHO grade were related to overall survival,while focal infil-tration and CNS WHO grade were the independent risk factors.Conclusion The prognosis of CNS WHO grade 3 PXA is wrose than that of grade 2 PXA.Accurate diagnosis of PXA requires the combination of the morphological features,immunohistochemical staining,and multiple molecular tests.

A 36-year-old male developed unconsciousness and no response to voice stimuli after taking approximately 2 050 mg felodipine (the specific time was unknown). Two hours later, he was sent to the department of emergency by his family and admitted to the hospital. His vital signs showed body temperature 35.1 ℃, pulse 148 times/min, respiration 32 times/min, and blood pressure 65/34 mmHg. Acute drug poisoning, acute toxic cardiomyopathy, acute toxic shock, acute type Ⅱ respiratory failure, acute toxic encephalopathy, and acute renal failure were diagnosed based on the patient′s clinical manifestations combined with laboratory tests results, cardiac ultrasound, chest and abdominal CT scans. Endotracheal intubation connected to a ventilator for invasive assisted ventilation, pressure boosting, and fluid resuscitation were given. At the same time, repeated gastric lavage and enema were performed to remove toxins. Blood perfusion was intermittently and repeatedly administered, and continuous renal replacement therapy was used. The blood concentration of felodipine was 1 298 μg/L at 2 hours after admission, and cardiac arrest occurred at 4 hours. Venous-arterial extracorporeal membrane oxygenation (V-A ECMO) treatment was administered immediately. After 48 hours of ECMO operation, sedatives were discontinued and the patient′s consciousness was improved after 4 hours. On the 5th day of ECMO treatment, his heart rate was 72 beats per minute, and blood pressure was 127/65 mmHg. The blood concentration of felodipine decreased to 2 μg/L. The patient′s vital signs were significantly improved and ECMO supportive treatment was withdrawn. After 26 days of hospitalization, the patient recovered and was discharged.

Objective To investigate the influencing factors of unplanned rehospitalization within one year after surgery among adult renal transplant recipients. Methods The clinical data of 299 recipients who underwent renal transplant surgery in the Department of Organ Transplantation of the Affiliated Hospital of Guizhou Medical University from January 2020 to December 2022 were retrospectively analyzed. The recipients were divided into unplanned rehospitalization group and non-rehospitalization group based on whether they experienced unplanned rehospitalization within one year after surgery. Univariate analysis and binary Logistic regression analysis were performed to explore the influencing factors of unplanned rehospitalization within one year after renal transplantation. Results Among the 299 recipients, 102 experienced unplanned rehospitalization, with an incidence rate of 34.11%. Univariate analysis revealedstatistically significant differences were noted between the two groups in terms of gender, occupational status, preoperative underlying disease, rejection reactions, nosocomial infections, immunosuppressive medication regimens, serum creatinine, cystatin C, serum phosphorus, serum potassium, and initial hospitalization duration (P < 0.05). Binary Logistic regression analysis showed that having ≥3 kinds of preoperative underlying disease (OR=2.122, 95%CI, 1.198 to 3.759) and experiencing rejection reactions (OR=3.162, 95%CI, 1.217 to 8.218) were independent risk factors for unplanned rehospitalization within one year after renal transplantation (P < 0.05). Conclusion The rate of unplanned rehospitalization within one year after surgery is relatively high among adult renal transplant recipients. Having ≥3 preoperative underlying disease and experiencing rejection reactions are independent risk factors for unplanned rehospitalization within one year after surgery. Transplantation healthcare teams can develop corresponding strategies targeting these risk factors to reduce the rate of unplanned rehospitalization and alleviate the burden of disease.

OBJECTIVES: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, which can lead to long-term cognitive impairment and anxiety in patients, and may even contribute to mortality in septic individuals. There is substantial individual variability in the incidence and severity and susceptibility of SAE, but the mechanisms regulating susceptibility remain unclear. Previous studies have shown that hippocampal damage is directly associated with cognitive and emotional disturbances in SAE. This study aims to explore the impact of hippocampal differentially expressed genes on SAE susceptibility in a mouse model. METHODS: Male specific pathogen-free (SPF)-grade C57BL/6 mice (6-8 weeks old) were randomly divided into a saline control group (Con group) and an SAE model group. SAE was induced by intraperitoneal injection of 10 mg/kg lipopolysaccharide (LPS), while control mice received an equivalent volume of saline. Cognitive and anxiety-like behaviors were assessed using the open field test (OFT), novel object recognition (NOR), and Y-maze test. Based on mean±standard deviation of behavioral results from the Con group, SAE mice were further classified into high-sensitivity (HS) and low-sensitivity (LS) subgroups. Immunohistochemistry was performed to detect the expression of immediate early gene c-Fos and neuronal marker neuronal nuclei (NeuN). Nissl staining was used to assess neuronal injury in the dentate gyrus (DG), cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) regions of the hippocampus. RNA sequencing (RNA-seq) was conducted on hippocampal tissues from HS and LS mice to identify differentially expressed genes, followed by pathway enrichment analysis. RESULTS: No significant behavioral susceptibility differences were observed between the overall SAE group and controls. However, HS mice showed severer cognitive deficits and anxiety-like behavior compared to LS mice. Immunohistochemistry revealed significantly higher expression of c-Fos in the hippocampus of LS mice (P<0.05), while Nissl and NeuN staining revealed milder neuronal damage in the hippocampus of LS mice than that of HS mice (both P<0.05). RNA-seq analysis identified 130 upregulated and 142 downregulated DEGs in LS and HS mice, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that upregulated genes in LS mice were primarily involved in pluripotency regulation, cyclic adenosine monophosphate (cAMP) signaling, and Wnt signaling pathways, in contrast, the downregulated genes were mainly related to cell adhesion, neuroactive ligand-receptor interaction, and calcium signaling pathways. CONCLUSIONS Differential gene expression in the hippocampus may contribute to individual susceptibility to cognitive and emotional dysfunction in SAE, suggesting potential genetic targets for individualized intervention.
Animals ; Sepsis-Associated Encephalopathy/genetics* ; Male ; Hippocampus/pathology* ; Mice, Inbred C57BL ; Mice ; Anxiety/genetics* ; Lipopolysaccharides ; Genetic Predisposition to Disease ; Disease Models, Animal ; Sepsis/genetics*