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    Innovative research team achievement column
    Promotive effect of cancer-testis antigen CT57 on proliferation, invasion, migration and epithelial-mesenchymal transition of liver cancer cells
    LUO Lange, ZHENG Chao, LEI Ming
    2024, 44 (11):  1335-1346. 
    doi: 10.3969/j.issn.1674-8115.2024.11.001

    Abstract ( 20 )   HTML ( 6 )   PDF (8853KB) ( 10 )  

    Objective ·To investigate the effect of cancer-testis antigen family member CT57 on proliferation, migration and invasion of the human liver cancer cells and tumorigenesis in nude mice, and the possible mechanism. Methods ·Bioinformatics methods were used to analyze the differential expression of CT57 in several cancer tissues and normal tissues, and its effect on the prognosis of liver cancer patients. Lentiviral vectors were used to establish liver cancer cell lines with stable knockdown and overexpression of CT57, which were confirmed by Western blotting. CCK-8 cell proliferation assay, soft agar colony formation assay and cell cycle experiment were used to detect the effect of CT57 on the proliferation and colony formation ability of liver cancer cells. Wound healing and Transwell assays were used to detect the effect of CT57 on the migration and invasion of liver cancer cells, and the expression of epithelial-mesenchymal transition (EMT) markers was detected by quantitative real-time PCR (qRT-PCR). To explore the effect of CT57 on liver cancer cells in vivo, CT57 knockdown liver cancer cells (experimental group) and control liver cancer cells (control group) were used to conduct subcutaneous tumor formation experiments in nude mice. Results ·Bioinformatics analysis of multiple tumors and corresponding normal tissues in The Cancer Genome Atlas Program (TCGA) database showed that CT57 was highly expressed in most tumor tissues, including liver cancer, and the expression level of CT57 was significantly correlated with the prognosis of liver cancer patients. Cell proliferation assay, soft agar colony formation assay, and cell cycle experiment showed that knockdown of CT57 inhibited the proliferation and colony formation of liver cancer cells and led to cell cycle arrest. In wound healing and Transwell assays, knockdown of CT57 inhibited the invasion and migration of liver cancer cells, while overexpression of CT57 promoted it. The results of qRT-PCR indicated that overexpression of CT57 resulted in downregulation of epithelial cell markers ECAD (E-cadherin) and OCLN (occludin), and upregulation of mesenchymal cell markers VIM (vimentin), TWIST1 (twist family bHLH transcription factor 1), and MMP2 (matrix metallopeptidase 2). In the in vivo experiments, knockdown of CT57 significantly reduced the tumor formation rate of liver cancer cells, tumor volume, and tumor weight in nude mice. Conclusion ·Knockdown of CT57 leads to cell cycle arrest, thereby inhibiting the proliferation of liver cancer cell and subcutaneous tumorigenesis in nude mice; CT57 promotes the invasion, migration and EMT of liver cancer cells.

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    Function and mechanism of cancer-testis antigen CT63 in chronic myeloid leukemia
    KONG Ruxin, ZHOU Yaqun, WEI Tingyi, LEI Ming
    2024, 44 (11):  1347-1358. 
    doi: 10.3969/j.issn.1674-8115.2024.11.002

    Abstract ( 25 )   HTML ( 4 )   PDF (22763KB) ( 11 )  

    Objective ·To explore the effects of the cancer-testis antigen (CTA) family member CT63 on proliferation, differentiation, and tumorigenicity of chronic myeloid leukemia (CML) cells, and uncover the underlying molecular mechanisms. Methods ·The link between CT63 expression and the prognosis of myeloid leukemia patients was analyzed using bioinformatics methods (TCGA database). A K562 cell line with CT63 knockdown was established. The knockdown efficiency of CT63 was confirmed by qRT-PCR and Western blotting. Live-cell imaging and CCK-8 methods were adopted to evaluate the inhibitory effect of CT63 knockdown in CML cells. A subcutaneous tumorigenesis assay in nude mice was conducted to examine the effects of CT63 on tumorigenesis, tumor growth, and differentiation of K562 cells invivo. Phorbol 12-myristate 13-acetate (PMA)-induced monocyte/macrophage differentiation experiment was carried out to investigate the role of CT63 in the differentiation of K562 cells in vitro. Mitochondrial function was assessed to determine the impact of CT63 on CML cells both in vivo and in vitro. Results ·The Kaplan-Meier survival curve indicated that low expression levels of CT63 were correlated with longer survival in patients with myeloid leukemia. Down-regulation of CT63 in K562 cells inhibited proliferation and promoted differentiation. Live-cell imaging and CCK-8 assays displayed that knockdown of CT63 inhibited cell proliferation and extended cell doubling time in K562 cells. In the subcutaneous xenotransplantation model, down-regulation of CT63 inhibited tumor growth in nude mice. K562 cells expressing lower levels of CT63 were more prone to differentiate into monocyte/macrophage both in vivo and in vitro under PMA exposure condition. Knockdown of CT63 suppressed the activity of mitochondrial respiratory chain complex Ⅳ. This led to decreased expression of mitochondrial markers, including cytochrome C oxidase Ⅳ (COX Ⅳ), pyruvate dehydrogenase, succinate dehydrogenase A (SDHA), and voltage-dependent anion channel (VDAC), thus affecting the mitochondrial metabolic activity of K562 cells. Conclusion ·CT63 is related to the prognosis of myeloid leukemia patients. CT63 plays an important role in promoting proliferation and inhibiting differentiation of K562 cells in vivo and in vitro. CT63 serves as a switch to regulate the balance between proliferation and differentiation of CML cells via the modulation of mitochondrial activity.

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    Basic research
    Mechanism of DUX-induced differentiation of mESC into extraembryonic endoderm
    HONG Lei, GUO Chuanliang, CAI Qin, LI Wanrui, ZENG Yitao, XUE Yan, ZENG Fanyi
    2024, 44 (11):  1359-1369. 
    doi: 10.3969/j.issn.1674-8115.2024.11.003

    Abstract ( 17 )   HTML ( 2 )   PDF (3532KB) ( 15 )  

    Objective ·To explore the effect of double homeobox (DUX) protein on the differentiation potential of mouse embryonic stem cells (mESCs) into extraembryonic endoderm (XEN) and the possible mechanism of its action. Methods ·Overexpression of DUX cell lines in mESCs was achieved by using a lentiviral system. The proportion of 2-cell-like cells (2CLCs) before and after DUX overexpression was detected by flow cytometry, and the expression of 2-cell stage-specific genes, Dux, zinc finger and SCAN domain containing 4c (Zscan4c), zinc finger protein 352 (Zfp352) and murine endogenous retrovirus-L polymerase (MERVL-pol), were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). RT-qPCR assay was used to detect the expression of pluripotency factors, nanog homeobox (Nanog), kruppel-like transcription factor 4 (Klf4), sex determining region Y-box 2 (Sox2), and octamer-binding transcription factor 4 (Oct4), in pluripotent state, as well as the expression of signature genes for different germ layers in the differentiated state [endodermal: GATA binding protein 4 (Gata4), GATA binding protein 6 (Gata6), and sex determining region Y-box 17 (Sox17); ectodermal: Nestin and tubulin beta 3 class Ⅲ (Tubb3); mesodermal: heart and neural crest derivatives expressed 1 (Hand1), myogenic differentiation 1 (Myod1), and kinase insert domain protein receptor (Flk1)]. Public RNA sequencing (RNA-seq) data were mined to further clarify the effect of DUX on the differentiation of mESCs into extraembryonic endoderm. Functional and pathway enrichment analyses of differentially expressed genes were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to identify the signaling pathways regulated by DUX. Additionally, an in-depth analysis of existing chromatin immunoprecipitation sequencing (ChIP-seq) data was conducted to explore the potential target genes of DUX. Results ·Molecular biology experiments showed that overexpression of DUX could effectively maintain the pluripotency of mESCs, which was consistent with the analysis of public RNA-seq data. Differential gene analysis revealed that endodermal genes were specifically upregulated. After differentiation assay of mESCs, RT-qPCR assay experiments showed that mRNA expression of the XEN marker genes (Gata4, Gata6, Sox17) was significantly upregulated (P<0.001). In contrast, there was no specific change in mesodermal and ectodermal genes. GSEA enrichment analysis indicated that DUX might activate the retinoid metabolism signaling pathway, and the analysis of the ChIP-seq data further revealed the presence of a large number of known retinoic acid receptor motif in DUX-bound peaks, which could activate downstream target genes related to the development of the XEN. Conclusion ·DUX has a strong correlation with the retinoic acid signaling pathway and it is predicted to activate the retinoic acid signaling pathway, which could promote the tendency of mESCs toward XEN differentiation.

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    Functional site analysis of mucin 1 in regulating the malignant characteristics of tumor cells
    GAO Kexing, LIAO Chunhua, LI Shengze, MA Shuangyu, HUANG Lei
    2024, 44 (11):  1370-1382. 
    doi: 10.3969/j.issn.1674-8115.2024.11.004

    Abstract ( 18 )   HTML ( 2 )   PDF (8623KB) ( 9 )  

    Objective ·To identify the functional motifs of mucin 1 (MUC1) involved in regulating tumor cell proliferation, migration, and stemness maintenance. Methods ·Mutational characteristics of the MUC1 gene across different cancers were identified from The Cancer Genome Atlas (TCGA) database. Various MUC1 mutation sites were analyzed and localized, followed by ranking based on mutation frequency. Western blotting was used to screen high-frequency MUC1 mutants with stable protein expression. BT549 cell line with MUC1 knocked out and MCF-10A cell line were used to stably overexpress MUC1 wild-type (MUC1-WT) and mutants by using lentiviral technology. Immunofluorescence was used to detect the cellular localization of MUC1 mutants. Using MUC1-WT as a positive control and MUC1-AQA, a loss-of-function mutant, as a negative control, the biological functions of different MUC1 mutant cells were analyzed: cell proliferation ability was assessed by cell counting kit-8 (CCK-8) assay and colony formation assay; cell migration ability was evaluated by wound-healing and Transwell assays; cell stemness was examined by sphere formation assay. Structural localization of MUC1 mutants was analyzed by using PyMOL software, and molecular docking analysis was performed by using a protein docking software (ZDOCK Server). ·Results A total of 102 mutations located in the MUC1 coding region were identified in the TCGA database, among which five missense mutations (P418S, S251R, V359I, N271S, and N465H) exhibited higher frequencies and were located in the non-variable number of tandem repeats (non-VNTR) region. Further examination revealed that the MUC1-S251R, N271S, and V359I mutants could be stably expressed. The cellular localization assay indicated that these three mutants predominantly localized in the cytoplasm, but were also presented in the nucleus. The nuclear-to-cytoplasmic ratio showed minimal differences between MUC1-WT and the mutants. Analysis of the tumorigenic biological functions of the cells expressing different MUC1 mutants revealed that: ① High expression of MUC1-WT significantly enhanced the proliferation ability of both BT549 and MCF-10A cells; the proliferation of MUC1-AQA, S251R, and N271S mutant cells was decreased compared to MUC1-WT cells, while MUC1-V359I mutant cells exhibited a similar proliferative profile to MUC1-WT cells. ② The migration ability of MUC1-WT high-expressing cells was significantly enhanced, whereas MUC1-AQA cells demonstrated attenuated migration. In the BT549 cells, the migration ability of MUC1-S251R and V359I cells was similar to that of MUC1-WT cells, whereas MUC1-N271S cells showed reduced migration. In the MCF-10A cells, the migration ability of MUC1-N271S and MUC1-V359I cells was similar to that of MUC1-WT cells, whereas MUC1-S251R cells exhibited significantly decreased migration. ③ Stemness was enhanced in both cell types with high MUC1-WT expression, while MUC1-AQA cells lost stemness; the cells with MUC1-N271S, V359I and MUC1-WT showed comparable maintenance of stemness, whereas MUC1-S251R cells demonstrated compromised stemness. PyMOL software analysis unveiled that MUC1-N271S and V359I were located in or around the sperm protein-enterokinase-agarin (SEA) region, specifically in the loop region and the β-sheet, respectively. The molecular docking analysis revealed that the stability of the complex formed by MUC1-WT or V359I with the extracellular domain of epidermal growth factor receptor (EGFR) surpassed that of MUC1-N271S or S251R, indicating a stability hierarchy of V359I>WT>N271S>S251R. ·Conclusion MUC1 mutants exhibit diverse impacts on the biological functions of tumor cells, with their effects on proliferation correlating with the EGFR signaling pathway. MUC1-V359I is similar to MUC1-WT, indicating a negligible effect on tumor cell proliferation, migration, and stemness maintenance. Conversely, MUC1-S251 and N271 sites may be involved in the regulation of signaling pathways governing cell proliferation and migration and the MUC1-S251 site plays a critical role in maintaining cell stemness.

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    Expression of MTA1 in preeclamptic placental tissue and its effects on trophoblast function
    GENG Yao, ZHANG Yang, ZHAO Jie, LI Wei, CAI Guoqing
    2024, 44 (11):  1383-1390. 
    doi: 10.3969/j.issn.1674-8115.2024.11.005

    Abstract ( 22 )   HTML ( 3 )   PDF (3077KB) ( 11 )  

    Objective ·To investigate the expression of metastasis-associated protein 1 (MTA1) in placental tissues of preeclampsia (PE) patients and its impact on trophoblast cell function. Methods ·Placental specimens were collected from pregnant women with PE (PE group, 20 cases) patients and healthy pregnant women as controls (control group, 35 cases). Western blotting and immunofluorescent double staining were performed to analyze the expression changes of MTA1. The human first-trimester placental trophoblast cell line HTR8/SVneo was cultured, and the cell migration ability was assessed through wound healing assay. The cell invasion ability was detected using Transwell invasion assay. Under hypoxic conditions simulating the invasion of extravillous trophoblasts into the uterus, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to analyze the mRNA expression of hypoxia-induced matrix metalloproteinases (MMP-2 and MMP-9), thus assessing their secretion levels. An extravillous trophoblast explant model was constructed to assess the overall villus outgrowth capacity of the explants. Immunohistochemistry (IHC) was performed to confirm the presence of the endothelial marker CD31 for placental angiogenesis analysis in mice. Fifteen Mta1-/- female mice and fifteen wild-type C57 female mice were mated with wild-type male C57 mice for fertility testing. Results ·Western blotting revealed significantly decreased expression of MTA1 protein in placental tissues of the PE group compared to the control group. Immunofluorescent double staining showed that MTA1 was mainly localized in the nuclei of trophoblast cells. The wound healing assay demonstrated that HTR8/SVneo with stable MTA1 knockdown exhibited weaker cell migration ability compared to the control group (P=0.002). The Transwell invasion assay demonstrated a marked decrease in invasiveness in MTA1-knockdown cells, significantly lower than the control group (P=0.015). Hypoxia-induced expression levels of matrix metalloproteinases MMP-2 and MMP-9 were significantly reduced (P=0.020, P=0.003). After MTA1 knockdown, the overall villus outgrowth capacity of the explants was decreased compared to the control group (P=0.003). IHC results showed that CD31 expression in the placenta of Mta1-/- female mice was significantly lower than that of wild-type female mice (P=0.004). The litter size of Mta1-/- female mice was significantly reduced (P=0.000). Conclusion ·The expression level of MTA1 is closely related to PE. Endogenous MTA1 may be involved in trophoblast invasion into the endometrium and villous capillary remodeling.

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    Nanoplastics aggravate severe asthma by inducing DNA damage of alveolar type Ⅱ epithelial cells
    SHI Zelun, WANG Qing, HE Wen, FU Weijia, WANG Yingwen, HAN Xiao, ZHANG Xiaobo
    2024, 44 (11):  1391-1405. 
    doi: 10.3969/j.issn.1674-8115.2024.11.006

    Abstract ( 21 )   HTML ( 2 )   PDF (7132KB) ( 8 )  

    Objective ·To explore the effects and possible molecular mechanisms of nanoplastics (NPs) on severe asthma. Methods ·A mouse model of severe asthma was established by using house dust mite (HDM) and lipopolysaccharide (LPS) co-stimulation. Polystyrene nanoplastics (PS-NPs) were instilled into the severe asthma mice′s airways. Subsequently, bronchoalveolar lavage fluid (BALF) was collected and lung tissue sections were prepared. Flow cytometry, hematoxylin-eosin (H-E) staining, periodic acid-Schiff (PAS) staining, immunohistochemistry, and terminal dexynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, were used to observe the effects of PS-NPs on airway inflammation, mucus secretion, alveolar structure, and the proliferation and apoptosis of alveolar type Ⅱ epithelial cells (AT2 cells) in severe asthma mice. The CCK-8 assay and Annexin Ⅴ/PI double staining were performed to evaluate the effects of PS-NPs on the proliferation and apoptosis of the mouse AT2 cell line MLE-12. DNA damage in AT2 cells caused by PS-NPs was detected by using anti-γ-H2A.X immunofluorescence staining. The expression of genes in the ATR/Chk1/p53 signaling pathway was detected by real-time fluorescent quantitative polymerase chain reaction (qPCR), Western blotting, Tyramide signal amplification (TSA) multiplex immunofluorescence staining, and immunofluorescence co-localization, respectively. The ATR-specific inhibitor Ceralasertib (AZD6738) was administrated to MLE-12 cells in combination with PS-NPs to evaluate the recovery effect on cell proliferation and apoptosis. Results ·Flow cytometry revealed that exposure to PS-NPs increased the total number of inflammatory cells and the number of each type of inflammatory cells in the BALF of mice with severe asthma, with a predominance of neutrophils. H-E and PAS staining showed significant increase in airway inflammatory cell infiltration and mucus secretion, as well as disruption of alveolar structure. In vitro, the CCK-8 assay demonstrated significant, dose-dependent inhibition of MLE-12 cell proliferation by PS-NPs. The Annexin V/PI double staining assay indicated a higher apoptosis rate of (56.20±3.84)% in PS-NP-exposed cells compared to (23.22±2.52)% in the control group. Immunofluorescence staining demonstrated that PS-NPs were phagocytosed by MLE-12 cells and localized around the nucleus. TUNEL staining confirmed enhanced apoptosis in AT2 cells in vivo. The immunofluorescence assay revealed that compared to the control group, the expression of the DNA damage marker γ-H2A.X increased in the experimental group. qPCR, Western blotting, and TSA multiplex staining results showed that PS-NP-induced elevated expression of mRNA and proteins was related to the ATR/Chk1/p53 pathway in MLE-12 cells. Moreover, immunofluorescence co-localization also confirmed the induction of ATR and p53 proteins in AT2 cells in vivo. The ATR-specific inhibitor Ceralasertib partially restored the PS-NP-induced inhibition of cell proliferation and enhancement of apoptosis in MLE-12 cells. Conclusion ·NPs exposure leads to DNA damage in AT2 cells, activating the ATR/Chk1/p53 signaling pathway and exacerbating airway inflammation and alveolar damage in mice with severe asthma.

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    Clinical research
    Analysis of clinical and genetic characteristics of 18 pediatric patients with Barth syndrome
    ZHAN Tianliu, YAN Zihang, WU Jinjin, CHEN Hao, CHEN Lijun, CHEN Yiwei, FU Lijun
    2024, 44 (11):  1406-1413. 
    doi: 10.3969/j.issn.1674-8115.2024.11.007

    Abstract ( 27 )   HTML ( 6 )   PDF (1638KB) ( 16 )  

    Objective ·To analyze the clinical and genetic characteristics of Chinese pediatric patients with Barth syndrome (BTHS) and provide data to support the prevention and treatment of BTHS. Methods ·Eighteen pediatric patients diagnosed with BTHS at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, from January 2010 to November 2023, were included. Clinical data (age, birth weight, family history, electrocardiogram, echocardiogram, urine tandem mass spectrometry, complete blood count, blood biochemistry, and genetic test results) were collected to analyze the clinical characteristics, genetic findings, and prognoses of the patients. Results ·The study included 18 male patients with BTHS (including 2 monozygotic twins), consisting of one Yi ethnic and 17 Han Chinese patients. The median age at diagnosis was 3.0 (1.0, 5.6) months. Fifteen patients experienced decreased cardiac function at disease onset, with a left ventricular ejection fraction (LVEF) below 50%. Dilated cardiomyopathy (DCM) was observed in 15 patients, left ventricular non-compaction (LVNC) in 12 patients, and myocardial hypertrophy in 9 patients. During the diagnosis and follow-up, QTc interval prolongation occurred in 9 patients, ventricular arrhythmias in 2 patients, neutropenia in 9 patients, and monocytosis in 10 patients. Urine tandem mass spectrometry revealed 3-methylglutaconic aciduria (3-MGCA) in 8 of 13 tested patients. Fifteen types of TAZ gene mutation were identified in the 18 patients, including 5 novel mutations. Genetic testing of the parents of 16 patients indicated maternal inheritance in 15 cases. The median follow-up period was 8.5 (2.6, 29.3) months, during which 12 patients died. The median age at death was 7.5 (6.0, 12.8) months. Causes of death included heart failure (7 cases, with 4 concurrent infections), sudden death (3 cases), ventricular fibrillation (1 case), and accidental death (1 case). Conclusion ·BTHS is a rare genetic disorder with multisystem involvement. Its primary clinical manifestations include cardiomyopathy and neutropenia. The condition typically presents early in life, with severe progression and poor prognosis. Prompt recognition, accurate diagnosis, and early intervention are essential for managing this disease.

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    Prediction of drug-drug interactions in clozapine combination therapy based on physiologically based pharmacokinetic model
    MOU Fan, HUANG Zhiwei, CHENG Yu, ZHAO Xue, LI Huafang, YU Shunying
    2024, 44 (11):  1414-1421. 
    doi: 10.3969/j.issn.1674-8115.2024.11.008

    Abstract ( 14 )   HTML ( 2 )   PDF (3039KB) ( 7 )  

    Objective ·To develop physiologically based pharmacokinetic (PBPK) models specifically designed for the Chinese population by utilizing the combination of clozapine and fluvoxamine as a case, and predict the drug-drug interaction (DDI) associated with the combination medication of clozapine, ultimately optimizing the dosage of clozapine. Methods ·By obtaining the physicochemical parameters, absorption, distribution, metabolism, excretion (ADME)-related parameters, and physiologically relevant parameters of the Chinese population through literature and pharmacology-related databases, PBPK models for the clozapine and fluvoxamine were constructed by using PK-Sim? software. The models′ accuracy was evaluated by comparing predicted values of the area under the curve (AUC) and peak concentration (Cmax) to observed data, using the mean percentage error (MPE) and mean absolute percentage error (MAPE) as evaluation indicators. The models were validated against real-world plasma drug concentration data. Additionally, combining the inhibitory effect of fluvoxamine on clozapine, models for the combination therapy of clozapine and fluvoxamine were developed to predict the pharmacokinetic changes of clozapine. The presence of clinically significant DDI was determined by using the 90% confidence interval of the AUC ratio (AUCR) or Cmax ratio (CmaxR) as evaluation metrics, with a non-effect boundary set at 80%?125%. The pharmacokinetic changes of clozapine upon co-administration with fluvoxamine based on PBPK models were quantified, and a dosage optimization for clozapine was developed. Results ·The constructed model of clozapine and fluvoxamine was considered accurate if the absolute value of the MPE was ≤10% and the MAPE was <25% during validation, indicating that the predicted concentration-time curves were accurate. The PBPK model for the co-administration of clozapine and fluvoxamine was able to accurately predict pharmacokinetic parameters if the ratio of predicted AUC to observed AUC was within 1.25. The prediction of PBPK model for the co-administration showed that the 90% confidence intervals for AUCR and CmaxR of the combination therapy of clozapine and fluvoxamine were not entirely within the ineffective effect boundary, indicating a clinically significant DDI when these two drugs were used concomitantly. Moreover, the dose optimization according to the PBPK models indicated that when subjects were co-administered with clozapine and fluvoxamine, reducing the dose of clozapine to 50% of the original dose could maintain the exposure levels of clozapine consistent with monotherapy. Conclusion ·The established PBPK model can effectively simulate the impact of combination therapy on pharmacokinetic changes of clozapine, providing valuable insights for predicting potential DDI and optimizing dosage regimens. If clozapine needs to be co-administered with fluvoxamine during the treatment, clinicians should remain vigilant for clinically significant DDI and contemplate optimizing the dosage of clozapine accordingly.

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    Effects of two rapid expansion methods combined with protraction on the treatment of skeletal class Ⅲ malocclusion in adolescents: a three-dimensional finite element analysis
    HAN Lei, LU Tong, ZHU Peixiang, LI Huang
    2024, 44 (11):  1422-1432. 
    doi: 10.3969/j.issn.1674-8115.2024.11.009

    Abstract ( 29 )   HTML ( 4 )   PDF (6456KB) ( 12 )  

    Objective ·To compare the effects of bone-anchored rapid expansion and tooth-borne rapid expansion combined with protraction on craniofacial sutures, skeletal points, bones and maxillary dentition using three-dimensional finite element analysis, and provide guidance for the clinical selection of appropriate traction methods and sites. Methods ·A cone beam computed tomography (CBCT) image of one adolescent with skeletal class Ⅲ malocclusion and maxillary hypoplasia during the mixed dentition period was selected to establish a three-dimensional finite element model of the maxillary complex (including craniofacial sutures, skeletal points, bones and maxillary dentition). Based on this, the three-dimensional finite element models of bone-anchored and tooth-borne rapid expansion combined with protraction were respectively established. Then, the aforementioned models were assembled into a three-dimensional finite element model of maxillary complex with bone-anchored rapid expansion combined with protraction (Model 1), and a three-dimensional finite element model of maxillary complex with tooth-borne rapid expansion combined with protraction (Model 2). According to the different expansion methods and protraction sites, the following conditions were set up: ① Based on the expansion methods, Model 1 was set as Group A, and Model 2 was set as Group B. ② Based on the protraction sites, Group A and B were further divided into experimental group Ⅰ(protraction hooks were placed buccally on both sides of the maxillary canines), experimental group Ⅱ(protraction hooks were placed buccally on both sides of the maxillary first premolars) and experimental group Ⅲ (protraction hooks were placed buccally on both sides of the maxillary second premolars), respectively. Additionally, as a control, Group A0 used bone-anchored rapid expansion alone without protraction, while Group B0 used tooth-borne rapid expansion without protraction. The stress distribution characteristics of craniofacial sutures in groups A and B at different protraction sites, as well as the displacement trends of craniofacial skeletal points, craniofacial bones and maxillary dentition were analyzed by using charts and tables. Results ·In terms of stress distribution characteristics of craniofacial sutures, pterygomaxillary suture′s equivalent strain was maximal in both groups A and B, and it increased when protraction hooks were placed backwards. The maximum principal strain value of each suture in Group AⅠ was larger than that in Group BⅠ. In terms of the displacement trend of craniofacial bones, as the protraction sites shifted posteriorly, both the nasal bones and maxilla in the horizontal direction moved rightward with decreasing displacement trends in both groups A and B. In the sagittal direction, the nasal bones moved posteriorly with decreasing displacement trends, while the maxilla moved anteriorly with increasing displacement trends in groups A and B. In the vertical direction, the nasal bones moved downward with decreasing displacement trends, and the maxilla moved upward with decreasing displacement trends in groups A and B. In terms of displacement trends of craniofacial skeletal points (ANS, PNS), the maxillary plane (ANS-PNS plane) in Group A underwent clockwise rotation, with the clockwise rotation trend decreasing as the protraction sites shifted posteriorly, while the maxillary plane (ANS-PNS plane) in Group B underwent counterclockwise rotation, with the counterclockwise rotation trend becoming more apparent as the protraction sites shifted posteriorly. In terms of the displacement trend of the maxillary dentition, the displacement of the central incisors in the horizontal, sagittal and vertical directions in the experimental groups A and B was all negative, presenting a tendency to move distally, labially and extrusively. The displacement of the first molar in the horizontal direction was also negative, indicating a trend of buccal displacement. Additionally, as the protraction site shifted posteriorly, the labial movement trend of the central incisors′ crown increased, and the crowns of the first molars changed from mesial to distal movement. Conclusion ·Clinically, placing protraction sites posteriorly is beneficial for the anterior movement of the maxilla. Adolescent with skeletal class Ⅲ malocclusion can choose different rapid expansion with protraction to achieve maxillary anterior displacement while realizing favorable rotation of maxillary plane.

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    Techniques and methods
    Analysis of accuracy and time for the two-in-one navigation registration technique in dynamic navigation implantation: an in vitro study
    XU Min, WEI Shimin, SHI Junyu, LAI Hongchang
    2024, 44 (11):  1433-1438. 
    doi: 10.3969/j.issn.1674-8115.2024.11.010

    Abstract ( 14 )   HTML ( 2 )   PDF (2445KB) ( 6 )  

    Objective ·To assess the accuracy and time of the two-in-one registration technique by comparing it with the U-shaped tube registration in dynamic navigation implantation. Methods ·Thirty standardized 3D-printed models with mandibular posterior sites missing a single tooth were randomly divided into three groups: two-in-one registration group, U-shaped tube registration group and free-hand implantation group, and the implant surgical plan was designed by the “YIZHIMEI” DCARER oral implant surgery navigation system. Cone beam CT before and after operation was taken. The implant platform deviation, implant apex deviation and angular deviation of the actual implant positions and the designed implant positions were measured. The operating time for using two-in-one registration technique and the U-shaped tube registration technique was recorded to evaluate the complexity of the two registration techniques. The one-way ANOVA and SNK (Student-Newman-Keuls) test were used to analyze the implant platform deviation, implant apex deviation and angular deviation of each group. Results ·There were no statistically significant differences in implant platform deviation, implant apex deviation and angular deviation between the two-in-one registration group and the U-shaped tube registration group (P>0.05). However, the implant platform deviation, implant apex deviation and angular deviation of the two-in-one registration group and the U-shaped tube group were lower than those in the free-hand implantation group, and the differences were statistically significant (P<0.001). The operating time required for the two-in-one registration was shorter than that for the U-shaped tube registration process, and the difference was statistically significant (P<0.001). Conclusion ·The accuracy of the two-in-one dynamic navigation registration technique used in implanting on a model of mandibular posterior sites missing a single tooth is similar to that of the U-shaped tube dynamic navigation registration technique. But the two-in-one registration takes less time for registration procedure than the U-shaped tube registration, and is easier to operate.

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    Review
    Research progress in the role of SIRT6 in aging and metabolism
    LIU Yonghui, TANG Li, LIANG Taigang, ZHANG Jian, FENG Li
    2024, 44 (11):  1439-1446. 
    doi: 10.3969/j.issn.1674-8115.2024.11.011

    Abstract ( 26 )   HTML ( 2 )   PDF (2240KB) ( 26 )  

    SIRT6, a member of the sirtuin family of histone deacetylases, belongs to the class Ⅲ longevity proteins and exhibits NAD+-dependent deacetylase and mono-ADP-ribosyltransferase activities. SIRT6 is primarily located in the cell nucleus and plays a pivotal role in regulating genomic stability and relative gene expression, participating in the control of key processes such as energy metabolism and aging. Given its crucial role in maintaining cellular homeostasis and organismal health, SIRT6 has emerged as a potential therapeutic target, sparking significant research interest in the development of targeted modulators. Activating the longevity protein with drugs may provide therapeutic strategies for age-associated diseases, including aging, metabolic syndrome, inflammation, and reproductive health issues. The review elaborates the structural characteristics, enzymatic activities, and biological functions of SIRT6, as well as the mechanisms of action, pharmacological activities, and clinical applications of various SIRT6 activators.

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    Research progress in behavioral paradigms on the symptoms of borderline personality disorder
    YANG Yang, QIU Jianyin
    2024, 44 (11):  1447-1453. 
    doi: 10.3969/j.issn.1674-8115.2024.11.012

    Abstract ( 27 )   HTML ( 3 )   PDF (1292KB) ( 11 )  

    Borderline personality disorder (BPD) is a type of personality disorder characterized by unstable emotion, self-consciousness and interpersonal relationships. Despite its high comorbidity with other mental disorders, interventions targeting BPD symptoms may aid in the treatment of the comorbid disorders, which makes BPD one of the most investigated personality disorders. Previously, BPD symptom features were mainly measured by standard scales, but the results of these scales would easily be affected by subjectivity or social desirability. One way to address this limitation is the application of behavioral paradigms, which can measure both explicit and implicit patterns of BPD patients in relatively true-to-life scenes more accurately and objectively. This article discusses behavioral paradigms related to four principal symptoms of BPD: interpersonal instability, emotional instability, identity disturbance and impulsivity, compares the differences in the results of these paradigms, and proposes possible directions for future BPD behavioral research, in order to achieve the enlargement of application of these paradigms. Combined with psychological, physical and pharmacal intervention, or other measurements such as functional near-infrared spectroscopy (fNIRS), eye tracking technology, functional magnetic resonance imaging (fMRI) or event-related potential (ERP), these paradigms would be able to uncover the inner cognitive and behavioral patterns of BPD patients, and improve the knowledge and understanding of researchers and mental health practitioners regarding BPD.

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    Research progress in drug repurposing in the treatment of breast cancer
    TAN Chen, XU Zhangrun, XUE Yang, CHEN Jiayu, YAO Lijun
    2024, 44 (11):  1454-1459. 
    doi: 10.3969/j.issn.1674-8115.2024.11.013

    Abstract ( 25 )   HTML ( 5 )   PDF (1279KB) ( 15 )  

    Breast cancer has become one of the most prevalent cancers among women worldwide, posing a significant burden on their health. Current standard therapies are often expensive and associated with the risk of drug resistance. Drug repurposing has gained increasing attention as a cost-effective and time-saving strategy in pharmaceutical research. Many drugs already in clinical use or undergoing clinical trials can be repurposed for the treatment of new clinical indications. Based on a comprehensive understanding of the mechanisms of action of these drugs and the pathophysiological processes of breast cancer, researchers can better identify drugs with potential anti-breast cancer properties and translate them into clinical practice. This paper provides a review of the current research on repurposing existing drugs for breast cancer treatment, summarizes the mechanisms of action of these drugs, and discusses the challenges associated with the strategy of drug repurposing.

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    Research progress of GALNT3 as a potential tumor molecular marker and drug target
    GAO Yixuan, ZHANG Yichi, DAI Luyan, MA Jiao
    2024, 44 (11):  1460-1465. 
    doi: 10.3969/j.issn.1674-8115.2024.11.014

    Abstract ( 41 )   HTML ( 7 )   PDF (1588KB) ( 19 )  

    Mucin-type O-glycosylation is one of the most common post-translational modifications in proteins, capable of altering protein conformation and biological functions. It plays a crucial role in biological processes such as cell signaling, cell adhesion, and immune responses. Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), as the initiating enzyme of mucin-type O-glycosylation, is of paramount importance in maintaining the homeostasis of human cells and tissues. Dysfunction of GALNT3 has been found to play a role in various diseases, such as calcium-phosphorus metabolism disorders and atherosclerosis. Additionally, GALNT3 is abnormally expressed in several types of tumors, including colorectal cancer, lung cancer, and ovarian cancer. Its expression is associated with the clinical pathological features of patients and poor prognosis, making it a potential biomarker for early tumor diagnosis and prognosis evaluation. Further research shows that GALNT3 can both regulate glycosylation levels to reduce adhesion between tumor cells and activate multiple metabolism-related pathways, promoting tumor cell invasion and metastasis. This review summarizes the role of GALNT3 in the development of malignant tumors and discusses the prospects and challenges of developing anti-tumor drugs targeting GALNT3.

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    Research progress in the role of DHX37 gene in disorders of sex development
    LIU Bei, HE Jing
    2024, 44 (11):  1466-1471. 
    doi: 10.3969/j.issn.1674-8115.2024.11.015

    Abstract ( 44 )   HTML ( 8 )   PDF (1312KB) ( 19 )  

    Disorders of sex development (DSD) are a group of conditions with strong clinical phenotype heterogeneity, and the incidence of DSD in the population is 1/5 000 to 1/4 500. According to the international classification standards, DSD is divided into sex chromosome DSD, 46,XY DSD and 46,XX DSD according to chromosomal karyotype. Only 35%?45% of patients with 46,XY DSD and 10% of those with 46,XX DSD have definite etiologies. So far, the phenotype and pathogenic mechanism of DSD are still the focus of research. DEAH-box helicase 37 (DHX37) is a novel candidate pathogenic gene for DSD, first identified in 2019. In recent years, researchers have confirmed that DHX37 gene variants are closely related to 46,XY DSD. DHX37 gene is one of the most conserved genes across genomes, making its genetic diagnosis difficult, and the molecular mechanism in causing 46,XY DSD is still unclear. In recent years, many researchers have screened the variation sites of the DHX37 gene by whole exome sequencing (WES) technology and explored its pathogenic mechanisms, which has expanded the genetic map of DSD. This article reviews the relationship between the structure and function of the DHX37 gene, the pathogenic mechanisms of clinical phenotypes and DSD caused by DHX37 gene variants. It also discusses the pathogenic mechanisms of human diseases in the context of ribosomal-related diseases caused by DHX37 gene variants.

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    Case report
    A case report of atypical anti-glomerular basement membrane disease with membrane hyperplasia lesions
    ZHANG Xinping, WANG Zichuang, CHEN Xiaoyong
    2024, 44 (11):  1472-1476. 
    doi: 10.3969/j.issn.1674-8115.2024.11.016

    Abstract ( 14 )   HTML ( 2 )   PDF (5695KB) ( 8 )  

    Atypical anti-glomerular basement membrane (GBM) disease is rare, and the atypical anti-GBM disease with membrane hyperplasia lesion is even rarer. The treatment plan for it is not clear. This article reports a case of atypical anti-GBM disease with a negative anti-GBM antibody test, but renal tissue biopsy showed “glomerular membrane hyperplasia lesions with positive IgG linearity”, which provides a reference for clinical diagnosis and treatment. The patient exhibited massive proteinuria, hematuria, edema, and renal impairment. After ruling out secondary factors, the patient was diagnosed with “atypical anti-GBM nephritis” by renal tissue biopsy, and was treated with glucocorticoids combined with cyclophosphamide, after which the patient developed a lung infection and acute left heart failure, and received regular hemodialysis treatment. Then the patient progressed to the stage of end-stage renal disease and continued to receive regular hemodialysis treatment.

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