Gastric cancer (GC) has high incidence and mortality worldwide. However, the underlying mechanisms that regulate gastric carcinogenesis are largely undefined. 4.1B is an adaptor protein found at the interface of membrane and the cytoskeleton. Previous studies demonstrated that 4.1B serves as tumor suppressor. We showed that 4.1B expression was decreased or lost in most GC patients. The expression pattern of it was tightly correlated with tumor size, TNM stage and overall survival (OS). We further showed that 4.1B inhibited the proliferation of two GC cell lines, MGC-803 and MKN-45, by impeding the EGFR/MAPK/ERK1/2 and PI3K/AKT pathways. A similar phenotype was also observed in immortalized mouse embryonic fibroblasts (MEF) derived from wild type (WT) and 4.1B knock-out (BKO) mice. Additionally, immunofluorescence (IF) staining and Co-IP showed that protein 4.1B bound to EGFR. Furthermore, the FERM domain of 4.1B interacted with EGFR through the initial 13 amino acids (P13) of the intracellular juxtamembrane (JM) segment of EGFR. The binding of 4.1B to EGFR inhibited dimerization and autophosphorylation of EGFR. Our present work revealed that 4.1B plays important regulatory roles in the proliferation of GC cells by binding to EGFR and inhibiting EGFR function through an EGFR/MAPK/ERK1/2 pathway. Our results provide novel insight into the mechanism of the development and progression of GC.

Objective: To described clinical and genetic characteristics of 4 patients presenting A20 haploinsufficiency (HA20) treated at Children’s hospital affiliated to Zhengzhou university from 2015 to 2024. Methods: A retrospective analysis was conducted on the clinical data, genetic testing results, and treatment outcomes of four children with HA20 treated at the Children’s hospital affiliated to Zhengzhou university from 2015 to 2024. Results: All four patients developed symptoms before the age of 1 year, presenting with recurrent fever and abdominal pain with diarrhea. Most common characteristics were hematochezia, bipolar aphthosis, arthritis, skin eruption in 50% of patients. Lab tests revealed elevated inflammatory markers; all patients had anemia. Imaging showed intestinal mucosal edema, hip/knee joint effusions, and lymphadenopathy in one case. Endoscopy revealed gastrointestinal aphthosis in 100% of cases. Genetic testing identified TNFAIP3 mutations in all four patients, including one novel whole-gene deletion (6q23.3chr6:136700000–138880000), 2 novel pathogenic mutations (c.866delA, c.1243_1247del), and one previously reported mutation (c.133C > T). Treatment included exclusive enteral nutrition (EEN) and thalidomide for all patients. One patient was switched to infliximab (IFX) combined with azathioprine due to gastrointestinal side effects, and one patient received methylprednisolone during acute phase. Follow-up for 4–10 years showed that 1 patient had improved symptoms with IFX and azathioprine but still had intermittent fever and perianal aphthosis; While one patient demonstrated poor response to EEN-thalidomide therapy requiring regimen change, the other responded well. One patient exhibited normalized gastrointestinal function following EEN-thalidomide therapy, yet still required repeated hospitalizations for recurrent infections with progressively prolonged inter-episode intervals. Conclusion: HA20 has strong clinical heterogeneity, and genetic testing is crucial for diagnosis and guiding treatment. Early diagnosis and individualized treatment can improve prognosis.

Lactate plays important regulatory roles in a variety of biological events by regulating metabolic homeostasis and histone lactylation. However, the role of lactate and histone lactylation in human erythropoiesis remains unclear. Here, we explored the role of lactate in erythropoiesis by adding the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) or exogenous lactate Na-La to decrease or increase intracellular lactate levels. The results showed the inhibition of glycolysis promoted erythroid progenitors’ differentiation, blocked cell cycle, and reduced colony formation of colony-forming unit-erythroid (CFU-E), whereas elevated lactate levels delayed erythroid progenitors’ differentiation and promoted CFU-E colony formation. We also found lactate levels directly regulated H3K14la intensity. Furthermore, we showed changes in H3K14la abundance and gene expression of the cell cycle and division-related genes CCNB1, CFL1, CENPA, and GNAI2, which were associated with stem cell pluripotency and differentiation. In conclusion, our study reveals lactate affects cell differentiation of early erythroid progenitors by regulating gene expression through histone lactylation.

Isocitrate dehydrogenase 1 (IDH1) is the key enzyme that can modulate cellular metabolism, epigenetic modification, and redox homeostasis. Gain-of-function mutations and decreased expression of IDH1 have been demonstrated to be associated with pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the function and mechanism of IDH1 in human erythropoiesis still remains unclear. Here, utilizing the human erythropoiesis system, we present an evidence of IDH1-mediated chromatin state reprogramming besides its well-characterized metabolism effects. We found that knockdown IDH1 induced chromatin reorganization and subsequently led to abnormalities biological events in erythroid precursors, which could not be rescued by addition of reactive oxygen species (ROS) scavengers or supplementation of α-ketoglutarate (α-KG).We further revealed that knockdown IDH1 induces genome-wide changes in distribution and intensity of multiple histone marks, among which H3K79me3 was identified as a critical factor in chromatin state reprogramming. Integrated analysis of ChIP-seq, ATAC-seq, and RNA-seq recognized that SIRT1 was the key gene affected by IDH1 deficiency. Thus, our current work provided novel insights for further clarifying fundamental biological function of IDH1 which has substantial implications for an in-depth understanding of pathogenesis of diseases with IDH1 dysfunction and accordingly development of therapeutic strategies.

To investigate the antibiotic resistance profile of Helicobacter pylori (H. pylori) strains and the CYP2C19 gene polymorphisms in initial eradication failure children from Henan, China (2019-2024). A retrospective cohort study included 207 children diagnosed with H. pylori infection by gastric mucosal histopathology. Participants were categorized by endoscopic findings: normal mucosa (NM), gastritis (GA), or peptic ulcer disease (PUD). Antimicrobial susceptibility testing was performed for amoxicillin (AML), furazolidone (FZD), metronidazole (MTZ), clarithromycin (CLA), tetracycline (TET), and levofloxacin (LEV). CYP2C19 genotyping was conducted via PCR. The annual number of cases increased from 13 in 2019 to 75 in 2024. Abdominal pain (89.4%) and loss of appetite (74.9%) were the most common symptoms. Endoscopic findings were primarily GA (57.0%). Resistance to FZD and TET was undetected (0%), and AML resistance was low (1.45%). High resistance rates were observed for MTZ (75.85%), CLA (75.36%), and LEV (22.22%). Dual MTZ+CLA resistance reached 61.35%, with the highest rate (18.1%) among 13-y-olds. Triple resistance (MTZ+CLA+LEV) was 16.43%. Both single and multidrug resistance increased significantly over time (P < 0.05). CYP2C19 genotyping revealed extensive metabolizers (EM, *1/*1) in 48.33%, intermediate metabolizers (IM, *1/*2+*1/*3) in 45.00%, and poor metabolizers (PM, *2/*2+*2/*3) in 6.67%. The high resistance rates to MTZ and CLA, coupled with the CYP2C19 EM phenotype, may contribute to the failure of initial empirical H. pylori eradication in children from Henan, China. Therefore, for retreatment, it is recommended to tailor an individualized regimen based on antimicrobial susceptibility testing and CYP2C19 genotyping results.