To explore the sex differences in drug metabolism of sufentanil in Chinese patients based on the mutation classification of cytochrome P450 3A (CYP3A) enzymes.

According to the possible effects of combined cytochrome P450 3A4 gene*1G locus (CYP3A4*1G) and cytochrome P450 3A5 gene*3 locus (CYP3A5*3) mutation groups on Chinese population, we added different weights to CYP3A4*1G and CYP3A5*3 polymorphisms and classified patients into 3 groups: Group Ⅰ, patients carried either the CYP3A4*1G/*1G allele or both CYP3A4*1/*1G allele and CYP3A5*3/*3 allele; Group Ⅱ, patients with both CYP3A4*1/*1G allele and CYP3A5*1/*3 allele; Group Ⅲ, patients with either the CYP3A4*1/*1 allele or both CYP3A4*1/*1G allele and CYP3A5*1/*1 allele. A single-dose, double-blind, stratified random sampling was performed, and 255 patients undergoing endoscopic surgery in the First Affiliated Hospital of Army Medical University were finally subjected. According to the results of genetic testing, an independent statistician, before operation, randomly selected 30 patients from each stratified group to form a study cohort (male-female ratio of 1∶1) and named each group A, B or C. Clinical investigators and subjects kept double-blind to the results of grouping and genetic testing. After entering the operating room, the subjected 90 patients received a single dose of sufentanil followed by collection of blood samples at 10 time points including 2 min before and from 2 to 120 min after administration. After the surgery, we determined the plasma drug concentration, calculated the pharmacokinetic parameters, and compared the metabolic differences between different genders in each group and unblinded the study.

The cohort best fitted the two-compartment pharmacokinetic model, and groups A, B and C corresponded to group Ⅰ, Ⅱ and Ⅲ, respectively. In different patient groups based on mutatron types of CYP3A enzymes the females had lower plasma drug concentration-time curves at each time point, higher systemic clearance (P≤0.01) and smaller area under the plasma concentration-time curve from zero to infinity (P<0.05) when compared with the males. In addition, in group Ⅰ, the elimination rate of central compartment and movement rate of drug from central compartment to peripheral compartment were obviously greater in the females than the males (P<0.05), while the distribution half-life (P<0.05) and elimination half-life (P<0.01) were notably longer in the males than the females. In both group Ⅱ and group Ⅲ, the males obtained larger total area under the plasma concentration-time curve than the females (P<0.05).

There are sex differences in the drug metabolism of sufentanil in Chinese patients. Women show faster distribution and higher clearance of sufentanil while men present greater drug exposure. Preoperative CYP3A genotyping and intraoperative personalized medication are of great significance to ensure the safety in clinical practice.

To develop models for predicting response to chemotherapy combined with immunotherapy in patients with esophageal squamous carcinoma with various machine learning algorithms, and then select the optimal model.

A retrospective study was performed for 174 patients with esophageal squamous cell carcinoma undergoing chemotherapy combined with immunotherapy admitted in Department of Thoracic Surgery of the First Affiliated Hospital of Army Medical University from January 2022 to December 2023. The CT scans and clinical information were collected before treatment. They were randomly divided into a training set (n=122) and a testing set (n=52) in a ratio of 7∶3. CT radiomic features were extracted and selected, and then 5 machine-learning algorithms were employed to establish the prediction models, including radiomics model and clinical-radiomics model. Five-fold cross-validation was conducted on the training set, and the performance of the prediction models was evaluated on the testing set using receiver operating characteristic (ROC) curve and the F1 score. The best-performing model was further explained using local interpretable model-agnostic explanations (LIME) algorithm.

Among the 174 patients, 115 (66.1%) achieved clinical remission. From the clinical information and CT images, 1 clinical features and 10 radiomic features were identified. The area under of ROC curve (AUC) for the radiomics and clinical-radiomics models was 0.750 (95%CI: 0.616~0.883), and 0.766 (95%CI: 0.637~0.895), respectively. The F1 score of the optimal clinical-radiomics model was 0.829. LIME algorithm indicated that this best model demonstrated reliability in predicting individual samples.

The clinical-radiomics prediction model based on machine learning algorithm performs well, and can provide a reference for doctors' clinical decision-making by predicting the response to chemotherapy combined with immunotherapy in patients with esophageal squamous cell carcinoma.

To provide an effective strategy for the prevention and treatment of radiation-induced infections by preparing platelet membrane-modified catalase/silica nanoparticles (PCNP) capable of targeting leukocytes.

PCNP and catalase/silica nanoparticles (CNP) were prepared by using platelet membrane, catalase (CAT) and silica, and its biological safety was preliminarily evaluated with cell survival test, hemolysis test and acute toxicity test in mice after tail vein administration; The culture medium, FITC labeled (FITC⁺) PCNP and FITC labeled (FITC⁺) CNP were co-incubated with human peripheral blood B lymphocytes (AHH-1) and mouse monocyte macrophages (RAW264.7), respectively. Thus, there were control group, FITC⁺ PCNP group and FITC⁺ CNP group of AHH-1 and RAW264.7 cells. Laser confocal microscopy was used to observe the intracellular fluorescence intensity of PCNP to evaluate the leukocytes targeting function. AHH-1 cells were divided into control, irradiation, platelet membrane, CNP (100 μg/mL) and PCNP (100 μg/mL) groups. After corresponding co-incubation, the cell media were exposed to6 Gy Co⁶⁰ γ irradiation. The generation of reactive oxygen species (ROS) and cell apoptosis were measured to determine the effect of nanoparticles on reducing radiation injury of leukocytes. Twenty C57BL/6 male mice (weighing 18~20 g) were randomly divided into irradiation group (n=10) and 10 mg/kg PCNP group (n=10). In 2 h after corresponding agents were injected into the mice through tail vein, the mice received whole-body irradiation of 5 Gy Co⁶⁰ γ ray, and then in 2 h later, they were given intraperitoneal injection of multidrug resistant Acinetobacterbaumannii (MDR-AB). The infection inhibitory effect of PCNP after irradiation was evaluated by detecting the bacterial load in main organs.

The hydration particle of PCNP is 91.3 nm in size, and does not exhibit significant cytotoxicity or hemolytic toxicity at concentrations <400 µg/mL. Intravenous injection of 20 mg/kg PCNP resulted in normal increase in the body weight but no obvious pathological changes in the major organs such as the heart, liver, spleen, lungs, and kidneys. In AHH-1 and RAW264.7 cells, PCNP showed significant advantages in targeting compared to the FITC⁺ CNP group [(15.45±3.48)% vs (9.33±2.03)%, P<0.01; (11.25±2.08)% vs (7.06±0.71)%, P<0.001]. PCNP also effectively reduced the generation of ROS [(22.73±3.71)% vs (60.90±9.08)%, P<0.001] and apoptotic rate [(9.84±0.92)% vs (38.96±3.62)%, P<0.001] in AHH-1 cells. In in vitro study, bacterial colonization after irradiation showed that there was significantly less MDR-AB colonies in the spleen of mice intervened with PCNP than those of the irradiation group [(17.50±1.38)×10⁴vs (13.20±2.29)×10⁶ CFU/g, P<0.001].

PCNP can effectively inhibit the complications of radiation infection in mice, which is due to its direct protective effect on leukocytes.

To conduct an in-depth analysis and feature extraction of the transcriptomics data of 10 types of cancers in order to realize the staging diagnosis of cancer samples.

The transcriptomics data of the top 10 cancers having the highest incidence were amassed from the UCSC Xena website, which comprised 4 938 samples and 59 428 genes. With the aid of variational autoencoder, we developed an incremental feature ranking and selection variational autoencoder (IFRSVAE) based on feature importance ranking and incorporating the masking algorithm and the Incremental Feature Selection (IFS). Subsequently, the performance efficiency of our IFRSVAE model was evaluated in conjunction with Random Forest (RF), Support Vector Machine(SVM), and eXtreme Gradient Boosting (XGboost), and it was also compared with other methods.

Our research extracted 21 features for the ensuing classification. In comparison to the conventional variational autoencoder, recursive feature elimination, and Lasso regression models, the IFRSVAE model attained more favorable performance across all 3 classifiers (highest AUC value, and well performed other indicators). Notably, the IFRSVAE-RF exhibited the most outstanding performance, with an AUC value reaching 85.49% (95%CI: 83.24%~87.74%). Moreover, Shapley additive explanations（SHAP） interpretable model illustrated well contributions of the features in our model.

Our developed IFRSVAE shows certain effectiveness in feature extraction. The constructed IFRSVAE-RF model demonstrates relatively good performance in the task of cancer staging diagnosis, which providing a new and referable idea for research orientation of deep-learning-based diagnostic methods for cancer staging.

To explore the association between single nucleotide polymorphism (SNP) of Rab37 gene and the age at menarche(AAM).

A case-control study design was used to conduct an epidemiologic survey on 2 060 women in a community in Jurong City, Jiangsu Province, and their venous blood samples were collected. ASA chip was used to explore the Rab37 gene genotyping of blood sample DNA to obtain the genotyping results for Rab37 SNPs rs62084865, rs10512597, rs35489971, rs1037170, rs6501732, rs77822106, and rs3178300. Based on menarche time of <16 years old or ≥16 years old, the participants were divided into 2 groups. Linear and logistic regression analyses were used to explore the association between the SNP of Rab37 gene and the age at menarche based on dominant, recessive and allelic models.

Among the 2 060 healthy women, 944 women had normal menstrual periods, while 1 116 women experienced delayed menarche. Linear regression analysis showed that the gene polymorphism of rs3178300 was negatively correlated with the age at menarche in females [recessive model: CC/CT+TT, β=-0.915, 95%CI(-1.692,-0.137), P=0.021; allelic model: T/C,β=-0.221, 95%CI(-0.410,-0.032), P=0.022]. Logistic regression analysis indicated that the gene polymorphism of rs3178300 was significantly associated with the risk of delayed menarche in females [recessive model: CC/CT+TT, OR=0.295, 95%CI (0.116,0.751), P=0.010; allelic model: T/C, OR=0.796, 95%CI(0.652,0.972), P=0.025]. The remaining 6 SNPs showed no significant association with age at menarche.

The rs3178300 polymorphism of Rab37 gene is significantly associated with delayed menarche in Chinese women.

To map the super-enhancers remodeling of intestinal gastric cancer and reveal the tumor biological functions of the super-enhancers and the downstream target genes that may be activated.

A total of 31 normal gastric mucosal tissues，23 intestinal gastric cancer tissues and 9 intestinal gastric cancer organoids were collected from the Department of Gastroenterology of Army Medical Center of PLA from January to December 2022. Chromatin targeting histone H3K27ac modified chromatin targeting cleavage under targets and tagmentation （CUT&Tag） sequencing was conducted on above tissues. The remodeling profiles of super-enhancers in intestinal gastric cancer were analyzed and the key target genes were identified based on bioinformation tools. CRISPRi technology was used to intervene with the super-enhancers，the expression of target genes was detected with Western blotting，and the proliferation，migration and invasion abilities were detected by CCK-8 assay and Transwell chambers in the control group and the intervention group.

There was a significant difference in the signal of super-enhancers between intestinal gastric cancer tissues and normal gastric mucosal tissues （P<0.05），and the active super-enhancers in cancer tissues may be involved in biological processes such as negative regulation of the immune system and cell adhesion. The expression of up-regulated cell migration-inducing protein （CEMIP） in tumor cells was regulated by the super-enhancers，and intervening the super-enhancers down-regulated the expression of CEMIP （P<0.05），and inhibited the cell proliferation，invasion and migration abilities of tumor cells （P<0.05）.

Super-enhancer remodeling is observed in intestinal gastric cancer，and they can up-regulate the expression of CEMIP gene and promote the growth，migration and invasion of cancer cells.

To investigate the diagnostic value of endoscopic sign of light blue crest (LBC) capsuling papillary lesion (LCPL) for high-risk intestinal metaplasia (IM).

A total of 314 patients (352 biopsy specimens) who underwent endoscopic examination and biopsy in Department of Gastroenterology of Army Medical Center of PLA from January 2021 to June 2023 were recruited, and HE and HID-AB staining (the golden standard of high-risk IM) were apllied to detect the histological types and IM types. The samples were subsequently divided into chronic inflammation group, low-risk IM group, high-risk IM group, well-differentiated intestinal-type gastric cancer group, and poorly-differentiated intestinal-type gastric cancer group. The positive rate of LCPL in each group and its diagnostic efficacy were analyzed based on endoscopic images of the biopsy sites. Logistic regression analysis was used to investigate the relationship between LCPL sign and high-risk IM, as well as the clinical and pathological features associated with LCPL sign. Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic efficacy of LCPL for high-risk IM, using indicators such as sensitivity, specificity, Youden index and area under the curve (AUC).

The positive rate of the LCPL sign in high-risk IM group was 75.70%, significantly higher than that of the other groups (all P<0.001). Logistic regression analysis showed that LCPL sign was significantly correlated with high-risk IM (OR=30.286, 95%CI: 13.528~67.804, P<0.001). When the sign was employed in diagnosing high-risk IM, the sensitivity was 69.84%, the specificity was 93.75%, the Youden’s index was 0.636, and the AUC value was 0.818 (95%CI: 0.773~0.857). Besides sensitivity, all above parameters of LCPL sign showed significantly better diagnostic efficacy than those of traditional LBC sign, which is used as a sign for diagnosing IM (P<0.001). Moreover, recognition of LCPL sign was not easily affected by age (OR=1.130, 95%CI: 0.709~1.800, P=0.607), lesion site (Angular incisure: OR=2.360, 95%CI: 0.732~7.613, P=0.151; Autrum: OR=2.257, 95%CI: 0.756~6.744, P=0.145), and presence of peptic ulcers (OR=1.085, 95%CI: 0.208~5.652, P=0.923). Significantly, 94.12% of positive and 66.94% of negative LCPL signs could be rapidly recognized within 3 s (OR=4.536, 95%CI: 1.372~14.997, P=0.013).

LCPL sign shows high efficacy and potential clinical application value for high-risk IM in gastric mucosa of endoscopic diagnosis.

To draw the genome-wide distribution and remodeling characteristics of H3K27me3 silencers in signet-ring cell carcinoma of the stomach (SRCC) through epigenetic sequencing technology, and to investigate their roles in transcriptional regulation in order to elucidate the regulatory mechanism of SRCC malignant progression.

The study was conducted on 35 gastric samples obtained by gastroendoscopic biopsy (15 normal and 20 SRCC tissues) from Department of Gastroenterology of Army Medical Center of PLA between January 2021 and December 2023. Multi-omics analyses, including assay for transposase-accessible chromatin with high-throughput sequencing （ATAC-seq), cleavage under targets and tagmentation （CUT&Tag) and transcriptome sequencing （RNA-seq), were performed to identify chromatin accessibility, H3K27me3 silencer regions, and transcriptional changes, with aid of Illumina NovaSeq 6000. H3K27me3 related differentially expressed genes (|Log₂FC|>1, FDR<0.05) were screened using DESeq2. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed to analyze the enrichment function, and Homer was employed to identify transcription factor motifs. A regulatory network was constructed using Cytoscape, and then validated using immunohistochemistry to explore its regulatory mechanism.

H3K27me3 silencers were primarily located in distal intergenic regions (37.06%) in SRCC. Compared with the normal tissues, SRCC showed a significant reduction in H3K27me3 silencer signals (95%CI:1.34~2.30, P=0.007) with 6 257 lost sites (FDR<0.01). Integrating CUT&Tag and RNA-seq revealed 380 up-regulated immune-related genes, particularly in T cell receptor signaling (OR=4.2, 95%CI: 2.8~6.3, P=0.002). Immunohistochemistry confirmed elevated expression of transcription factor EHF (P<0.05).

There is the remodeling of H3K27me3 silencers in SRCC, and EHF may potentially play a crucial role in the SRCC malignant progression.

To identify the enhancer profile marked by histone H3K27ac modification in high-grade intraepithelial neoplasia (HGIN) in order to reveal the novel regulatory mechanism of HGIN pathogensis.

Gastric tissue samples were collected from Department of Gastroenterology of Army Medical Center of PLA between June 2022 and June 2023, including 14 normal gastric tissues (Nor group), 31 HGIN tissues (HGIN group) and 17 gastric cancer tissues (GC group). Cleavage under targets and tagmentation (CUT&Tag) technique was employed to capture enhancer regions modified by histone H3K27ac. Multi-omics analysis was performed to identify HGIN-specific active enhancers and their potentially regulated genes. Immunohistochemical profiling was performed to assess differential expression of the gene of interest across clinically stratified specimens, combined with CRISPR-dCas9-mediated ablation of active enhancers to monitor the gene of interest transcriptional dynamics and validate enhancer-mediated regulatory mechanisms.

Epigenomic sequencing obtained the data with excellent quality, and indicated that obvious remodeling was observed in H3K27ac enhancers in HGIN and GC groups (P<0.05), though no significant difference in the genome-wide distribution of H3K27ac modification among the 3 groups.Combining transcriptome data revealed that enhancer remodeling may up-regulate the expression of the proliferation-related target gene, CD24, in the HGIN tissue; while, inhibiting enhancer activity can notably reduce CD24 expression level (P<0.05). Immunohistochemical assay displayed a positive correlation between the expression levels of CD24 and Ki-67 (P<0.001).

The remodeling of H3K27ac enhancer represents a significant epigenetic feature of the transformation from normal condition to HGIN. Remodeling of H3K27ac enhancer up-regulates CD24, which may facilitate the abnormal proliferation of gastric epithelial cells.