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    Pediatric asthma column
    Exploratory analysis of gut microbiota differences in childhood asthma with different severity
    WEN Yajin, HE Wen, HAN Xiao, ZHANG Xiaobo
    2023, 43 (6):  655-664. 
    doi: 10.3969/j.issn.1674-8115.2023.06.001

    Abstract ( 281 )   HTML ( 31 )   PDF (3425KB) ( 501 )  

    Objective ·To explore the characteristics and differences of gut microbiota in children with different severity of bronchial asthma, and build a prediction model of gut microbiota in severe asthma. Methods ·In this study, children aged 5 to 14 diagnosed with asthma in the Department of Respiratory Medicine of Children's Hospital of Fudan University from Sep 1, 2020 to Aug 31, 2022 were selected, and children with severe asthma (SA) according to the Recommendations for Standardized Diagnosis and Managementof Bronchial AsthmainChildren (2020) were included. Children with mild to moderate asthma (MMA) and healthy children in the same period were matched according to age and gender. Stool samples collected from the three groups were subjected to 16S rRNA gene sequencing and the gut microbiota diversity, structure, and composition were assessed. The area under the receiver operating characteristic (ROC) curve (AUC) was applied to compare the predictive efficacy for SA. Results ·Fifty children were enrolled in the SA group, 54 children matched by gender and age were in the MMA group and 39 healthy children were in the healthy control group. The α diversity of gut microbiota significantly decreased in the asthma children (P<0.05), compared with that in the healthy control group. The relative abundance of Treponema was the highest in the SA group, followed by the MMA group and healthy control group (P<0.001). The relative abundance of Lactobacillus in the MMA group and SA group was higher than that in the healthy control group (both P<0.05). The SA group had a higher relative abundance of Prevotella, Lactobacillus, Eubacterium_eligens_group, Treponema, and Fusicatenibacter. The MMA group had a higher relative abundance of Barnesiella, Holdemanella, Romboutsia and Turicibacter. The healthy control group had a higher relative abundance of the uncultured and Muribaculaceae. Among them, the relative abundance of Barnesiella decreased in the SA group, and itwas found to have the highest sensitivity and specificity in predicting SA (AUC 0.713, 95%CI 0.604?0.815). Conclusion ·The diversity of gut microbiota in asthma children is lower than that in healthy children, and the composition of gut microbiota differs among childhood asthma with different severity. The abundance of Barnesiella decreases in the SA group significantly, suggesting that analysis of gut microbiota may help in the assessment of childhood asthma with different severity.

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    Epidemiological characteristics and risk factors of severe asthma in children: a single-center prospective cohort study
    WANG Yingwen, LI Xiaoling, DAI Jiajia, LIU Fang, HUANG Jianfeng, WANG Libo, ZHANG Xiaobo, FENG Rui
    2023, 43 (6):  665-672. 
    doi: 10.3969/j.issn.1674-8115.2023.06.002

    Abstract ( 358 )   HTML ( 28 )   PDF (1773KB) ( 256 )  

    Objective ·To explore the epidemiological characteristics of severe asthma in children and analyze the risk factors. Methods ·A single-center prospective cohort study was conducted. Six hundred and seventy four children with difficult-to-treat asthma who visited the Children′s Hospital of Fudan University from January 1 to December 31, 2021 were included to establish a dynamic cohort. Basic information (including gender, age, gestational age at birth, birth weight, etc.) and comorbidity of the cohort members were collected. The asthma control status, drug inhalation technique level, medication compliance, pulmonary function parameters [forced expiratory volume in one second (FEV1) as a percent-age of the predicted value (FEV1%pred), FEV1/ forced vital capacity (FVC), and the rate of estimated values of forced expiratory flow at 50% of FVC exhaled (FEF50), FEF75, and FEF25-75 in percent-predicted value, respectively], airway inflammation index [fraction exhaled nitric oxide (FeNO)], and allergy status parameters [eosinophil (EOS) and immunoglobulin E (IgE)] of all cohort members were evaluated. All cohort members underwent re-evaluation respectively at the specialist asthma clinic of the hospital at 3, 6, 9, and 12 months. Results ·At the endpoint of the cohort, 52 children were diagnosed with severe asthma, accounting for 7.7%. A high proportion of severe asthma was found in children who were exposed to secondhand smoke, used air conditioning at home all year round, or had coexisting rhinitis/nasosinusitis, FEV1%pred<80%, FEV1/FVC<80%, small airway dysfunction, EOS>300/μL, IgE>200 IU/L, or FeNO>20/25 ppb [FeNO>20 ppb (≤12 years old) or >25 ppb (>12 years old), 1 ppb=1×10-9 mol/L]. A high proportion of non-severe asthma was found in children who were breastfed for 6 months or longer, or had good medication compliance. The differences were statistically significant (all P<0.05). There were more males in children with severe asthma aged 6?11 years, and more females in children with severe asthma aged 12?17 years, with statistical significance (both P<0.05). Multiple-factor Logistic regression analysis showed that only small airway dysfunction was an independent risk factor for severe asthma [OR=5.158 (95%CI 2.516?10.572)]. Conclusion ·The proportion of children with severe asthma has a significantly decrease after one year of standardized management in children with difficult-to-treat asthma. Small airway dysfunction is an independent risk factor for the progression to severe asthma.

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    Clinical study of exhaled nitric oxide in children with asthma and allergic rhinitis
    LI Pengyun, DAI Yinfang, LU Yanhong, YU Xingmei, XU Lina, DI Wujianfeng, HAO Chuangli
    2023, 43 (6):  673-679. 
    doi: 10.3969/j.issn.1674-8115.2023.06.003

    Abstract ( 225 )   HTML ( 18 )   PDF (1382KB) ( 152 )  

    Objective ·To determine the levels of nasally exhaled nitric oxide (FnNO) combined with fractional concentration of exhaled nitric oxide (FeNO) in children with asthma (AS) complicated with allergic rhinitis (AR), and analyze the levels of FnNO and FeNO in different clinical stages of AS with different severities of AR, so as to provide basis for guiding clinical diagnosis and treatment. Methods ·Children diagnosed with AR with AS in the Department of Respiratory and Otolaryngology of Children's Hospital of Soochow University from April 2021 to November 2021 were included, and healthy children who visited the Department of Pediatrics for normal physical examination during the same period were enrolled as the control group. FeNO and FnNO were measured in all children to assess the severity of the children's diseases. The levels of FeNO and FnNO in children with AR and AS at different clinical stages of AS and their correlation with pulmonary function were compared and analyzed. Results ·The proportion of persistent moderate-to-severe rhinitis was higher in the acute exacerbation stage of AS, and the proportion of intermittent mild rhinitis was higher in the clinical remission stage of AS. The FeNO level in the acute exacerbation stage were higher than that in the chronic persistent stage and clinical remission stage of AS (adjusted P=0.022, 0.000), and higher in the chronic persistent stage than that in the clinical remission stage of AS (adjusted P=0.002). The FnNO level in the acute exacerbation stage was higher than that in the clinical remission stage of AS (adjusted P=0.044). In the chronic persistent stage of AS, the FnNO levels in the persistent mild group and persistent moderate-to-severe control group were higher than those in the intermittent mild group (adjusted P=0.001, 0.000). In the clinical remission stage of AS, the FnNO levels in the persistent mild group and persistent moderate to severe control group were higher than those in the intermittent mild group (adjusted P=0.001, 0.007). In the intermittent mild group of AR, the FnNO levels in the acute exacerbation stage were higher than those in the chronic persistent stage and clinical remission stage of AS (adjusted P=0.010, 0.019). Part of pulmonary functions in the acute exacerbation stage of AS children were negatively correlated with the FeNO and FnNO levels (all P<0.05), while FEV1/pred in the chronic persistent stage was negatively correlated with FeNO level (P=0.010). Conclusion ·FeNO and FnNO levels increased in the acute exacerbation stage of AS, and symptom scores of AR also increased. FeNO and FnNO levels were negatively correlated with pulmonary function in AS with AR children.

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    Diagnostic value of fractional exhaled nitric oxide in predicting cough variant asthma in children with chronic cough: a systematic review and meta-analysis
    DANG Xiangyang, TANG Yuyi, LI Weiguo, LIU Enmei
    2023, 43 (6):  680-688. 
    doi: 10.3969/j.issn.1674-8115.2023.06.004

    Abstract ( 221 )   HTML ( 20 )   PDF (2861KB) ( 193 )  

    Objective ·To evaluate the values of fractional exhaled nitric oxide (FeNO) for the diagnosis of cough variant asthma (CVA) in children with chronic cough by systematic review and meta-analysis. Methods ·PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Database (SinoMed), China National Knowledge Infrastructure (CNKI), and Wanfang Database were systematically searched for cohort studies and case-control studies to March 1, 2022. Two researchers independently screened the studies according to the inclusion and exclusion criteria, and the number of true positive, false positive, true negative, and false negative patients and the cut-off value of FeNO were extracted from the studies. Diagnostic accuracy studies tool version 2 (QUADAS-2) was used to evaluate the quality of the included literature in terms of risk bias and clinical applicability. Revman 5.4 was used to draw the quality evaluation chart. A meta-analysis was performed by the midas and spearman commands of Stata 17.0. Spearman correlation coefficients of sensitivity logarithm and (1-specificity) logarithm were used to test the threshold effect. The substantial heterogeneity caused by non-threshold effect was tested by bivariate box plot and I2 statistic. The effect size was pooled by bivariate random effect model. Publication bias was evaluated by Deek′s Funnel plot. Results ·One thousand and ninety-nine studies were retrieved in total and 9 were finally included. The diagnostic criteria of the included study were all from expert consensus or guidelines. The QUADAS-2 showed that the quality of the included study was low. The Spearman correlation coefficient of sensitivity and (1-specificity) was 0.05 (P=0.90), indicating that there was no heterogeneity caused by threshold effect. The results ofbivariate box plot and I2=0 showed that there was no heterogeneity caused by non-threshold effect. Combined effect showed that the sensitivity was 0.82 (95%CI 0.78-0.85), the specificity was 0.93 (95%CI 0.89?0.95), the positive likelihood ratio was 11.30 (95%CI 7.40?17.10), the negative likelihood ratio was 0.19 (95%CI 0.16?0.24), the diagnostic odds ratio was 58 (95%CI 34?101), and the area under the summary receiver operating characteristic (SROC) curve was 0.89 (95%CI 0.86?0.92). The result of Deek′s Funnel plot showed that there was no publication bias. Conclusion ·FeNO test has a moderate diagnostic value in prediciting CVA in children with chronic cough. However, the results of the study need to be interpreted with caution due to the low quality of the original evidence.

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    Basic research
    Construction and characterization of mice with conditional knockout of Stat3 gene in microglia
    ZHU Xiaochen, XIE Xinyi, ZHAO Xuri, XU Lina, HE Zhiyan, ZHOU Wei
    2023, 43 (6):  689-698. 
    doi: 10.3969/j.issn.1674-8115.2023.06.005

    Abstract ( 878 )   HTML ( 47 )   PDF (6326KB) ( 563 )  

    Objective ·To construct mice with conditional knockout of Stat3 gene in microglia based on the Cre-Loxp system and validate their knockout efficiency. Methods ·Cx3cr1creERT2 and Stat3fl/fl genotypic mice were bred for conditional knockout mice (CKO) and Wild Type mice (WT). The mouse genotypes were determined by extracting DNA from mouse tissues through Polymerase Chain Reaction (PCR) combined with the amplification results of cre and flox primers. Stat3 knockdown was induced by intraperitoneal injection of tamoxifen in the CKO and WT mice at 6 weeks of age. The CKO mice (n=4) and WT mice (n=4) were randomly selected for the detection. After two weeks of observation, microglia cells were sorted out by Magnetic Activated Cell Sorting (MACS). Real-time PCR (RT-PCR) was used to detect gene knockout efficiency at the gene level. The expression of STAT3 in microglia was observed by brain immunofluorescence staining. The expression rate of STAT3 in microglia was detected by flow cytometry. The expression rate of STAT3 in macrophages of the spleen was detected by flow cytometry. The condition of neuronal cells was examined by Nissl staining. The condition of the microglia in the cortex and hippocampus was observed by brain immunofluorescence staining. The phenotype of the microglia was detected by flow cytometry. Results ·The CKO mice and WT mice were successfully bred. MACS boosted the proportion of microglia in brain cells from 10% to 85%. RT-PCR results showed that mRNA levels of Stat3 were down-regulated in microglia of CKO mice, compared with the WT mice (P=0.001). The relative mRNA expression of Stat3 in microglia of the CKO mice was 0.331 7±0.041 4. Immunofluorescence staining of brain tissues showed that the fluorescence intensity of STAT3 in microglia of the CKO mice was weaker than that of the WT mice. Flow cytometry of brain tissues showed that the STAT3-positive cells in microglia of the WT mice was (85.30±5.69)% and the CKO mice was (39.70±3.88)%. STAT3 expression was decreased in microglia of the CKO mice (P=0.001). Flow cytometry of spleen tissues showed that there was no statistical difference in the percentage of STAT3-positive cells in splenic macrophages between the CKO and WT mice (P>0.05). Nissl staining showed that there were no significant differences between the neuronal cells of the CKO mice and WT mice. Immunofluorescencestaining of brain tissues showed that there was no significant difference in the shape of microglia between the CKO mice and WT mice. Flow cytometry showed that the phenotype of microglia in the CKO mice was not remarkably different from that of the WT mice. Conclusion ·We successfully construct the STAT3 gene conditional knockout mice from microglia, which provides the foundation for subsequent related studies.

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    miR-185-5p facilitates intracellular Mycobacterium growth via inhibiting macrophage autophagy
    WU Qiqi, WANG Hao, LIN Li, YAN Bo, ZHANG Shulin
    2023, 43 (6):  699-708. 
    doi: 10.3969/j.issn.1674-8115.2023.06.006

    Abstract ( 258 )   HTML ( 26 )   PDF (3396KB) ( 162 )  

    Objective ·To explore the regulatory effect of miR-185-5p on autophagy in Mycobacterium-infected macrophages and its influence on the survival of intracellular Mycobacterium. Methods ·Macrophages derived from human monocytic-leukemia (THP-1) cells were infected with Bacillus Calmette-Guérin (BCG) strain. Exosomes from cell culture supernatant were isolated by ultracentrifugation, and exosome surface marker proteins, size and morphology were detected by Western blotting, nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM), respectively. The expression level of miR-185-5p in both macrophages and exosomes was detected by real time quantitative polymerase chain reaction (qPCR). The exosomes were labeled with the fluorescent dye PKH26 and co-cultured with macrophages to observe the phagocytosis of exosomes by macrophages. Subsequently, the overexpression and inhibition of miR-185-5p in macrophages were achieved by transfecting cells with miR-185-5p mimic and inhibitor, and the influence of miR-185-5p on intracellular BCG survival was detected by colony-forming units (CFU) assay. Autophagy marker microtubule-associated protein 1 light chain 3 (LC3) protein was detected by Western blotting.The effects of overexpression and inhibition of miR-185-5p and the use of autophagy inhibitor chloroquine (CQ) on macrophage autophagy were studied. The SensGFP-StubRFP-LC3 lentvirus was further employed to detect the effect of miR-185-5p on autophagic flux. Finally, TargetScan, miRDB and Starbase databases were used to predict the target genes of miR-185-5p, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis of these predicted target genes. Results ·The macrophage exosomes were isolated by ultracentrifugation. Exosome marker proteins cluster differentiation 9 (CD9) and tumor susceptibility gene 101 (TSG101) were successfully detected by Western blotting. The exosomes had a bilayer membrane with a diameter of approximately 150 nm through TEM and NTA identification. After BCG infection, the expression of miR-185-5p was up-regulated in both macrophages and exosomes (P=0.000), and showed a time-dependent increase in macrophages. Exosomes, which were co-cultured with macrophages, can be phagocytized by macrophages. Compared with respective control of mimic and inhibitor, mimic significantly up-regulated miR-185-5p expression (P=0.000), while inhibitor inhibited miR-185-5p expression (P=0.002). miR-185-5p mimic significantly increased the number of CFU of intracellular BCG (P=0.000), while miR-185-5p inhibitor decreased the number of CFU (P=0.041). BCG infection up-regulated the expression of autophagy protein LC3Ⅱ in macrophages, while LC3Ⅱ expression was decreased by miR-185-5p mimic and increased by miR-185-5p inhibitor. CQ treatment combined with miR-185-5p inhibitor transfection still significantly increased LC3Ⅱ expression in macrophages. The SensGFP-StubRFP-LC3 lentivirus was further used to detect autophagy flux, and it was suggested that, compared with that in the respective control group, mimic significantly reduced the formation of autophagosomes (P=0.034), while inhibitor increased the formation of autophagosomes (P=0.042). Through target genes prediction and GO and KEGG functional enrichment analysis, it was found that miR-185-5p might play a role in autophagy regulation by targeting nuclear receptor subfamily 1 group D member 1 (NR1D1), Ras-related protein Rab-35 (RAB35), cell division control protein 42 homolog (CDC42), etc. Conclusion ·Mycobacterium infection can induce the up-regulation of miR-185-5p in both macrophages and exosomes, and miR-185-5p can inhibit the autophagy process of macrophages by inhibiting the formation of autophagosomes, which can promote the growth and survival of intracellular Mycobacterium.

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    RBX1 regulates uveal melanoma immune-related genes via STAT1
    ZHOU Xiaowen, LI Qian, ZHANG Zhe, SHEN Jianfeng, FAN Xianqun
    2023, 43 (6):  709-717. 
    doi: 10.3969/j.issn.1674-8115.2023.06.007

    Abstract ( 307 )   HTML ( 33 )   PDF (3226KB) ( 269 )  

    Objective ·To investigate the role of RBX1 (ring-box protein 1) in the regulation of immune-related genes in uveal melanoma (UVM) tumor cells. Methods ·The Cancer Genome Atlas (TCGA) was searched to analyze the expression levels of RBX1 in tumors and the correlation with clinical stages and survival prognosis. RBX1 was transiently knocked down in the UVM cell lines, i.e., 92.1, OMM2.3 and MEL290 by using small interfering RNAs (siRNAs) targeting RBX1. RNA sequencing was performed on the 92.1 cells with transient knockdown of RBX1, and the differentially expressed genes between the siRBX1-transfected cells and control cells were analyzed by gene set enrichment analysis (GSEA) to investigate the relationship between RBX1 and tumor immune-related genes. Based on the results of the analysis, signal transducer and activator of transcription 1 (STAT1) and its downstream CXC chemokine ligand 9 (CXCL9) and CXCL10 mRNA expression levels were detected by real-time fluorescence quantitative PCR (qPCR) in 92.1, OMM2.3 and MEL290 cells with transient knockdown of RBX1, respectively. The protein expression levels of STAT1 and p-STAT1 in 92.1 cells were detected by Western blotting. The cell lines OMM2.3 and MEL290, in which RBX1 was transiently knocked down, were treated with 5 nmol/L or 10 nmol/L STAT1 inhibitor fludarabine for 48 h, and the mRNA expression levels of CXCL9 and CXCL10 were detected by qPCR. Results ·TCGA database analysis showed that RBX1 was highly expressed in a variety of tumors compared to the normal tissues, particularly in adrenocortical carcinoma and UVM. In addition, the patients with late stage of these two kinds of tumors had higher expression level of RBX1, and the patients with higher expression level of RBX1 had shorter overall survival time (P<0.05). RNA sequencing of 92.1 cells with transiently knocked down RBX1 and control cells revealed differential genes, and GSEA showed that RBX1 was involved in the regulation of tumor immune-related pathways. Heat map analysis showed an increase in STAT1 expression after RBX1 knockdown. In the 92.1, OMM2.3 and MEL290 cell lines, qPCR showed increases in STAT1, CXCL9 and CXCL10 mRNA expression after transient knockdown of RBX1, and Western blotting showed that STAT1 and p-STAT1 expression increased after knockdown of RBX1 in 92.1 cell lines. The increases of CXCL9 and CXCL10 mRNA in OMM2.3 and MEL290 cell lines were suppressed by STAT1 inhibitors. Conclusion ·RBX1 may regulate CXCL9 and CXCL10 expression via STAT1 in UVM cells and is involved in tumor immune regulation.

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    Enhancement of the neutralization ability resulting from a single amino acid change in the light chain of a chimeric antibody against SARS-CoV-2
    YIN Zi, LIAN Chaoyang, GAO Bo, TIAN Ying, HAO Qian, YEAP Lengsiew
    2023, 43 (6):  718-727. 
    doi: 10.3969/j.issn.1674-8115.2023.06.008

    Abstract ( 236 )   HTML ( 18 )   PDF (3448KB) ( 158 )  

    Objective ·To screen the human-mouse chimeric antibodies that neutralize the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and analyse the key amino acid site changes in their light chain. Methods ·Antibody heavy chain gene-humanized mice were immunized with the spike protein of SARS-CoV-2. Enzyme-linked immunosorbent assay (ELISA) and pseudovirus neutralization assay were performed to analyse the antibody titer in serum level. Flow cytometry was used to sort plasma cells and germinal center (GC) B cells from the mouse spleen and lymph nodes, and the proportions of different B cells were analysed. RNA was extracted to construct a mouse-origin antibody light chain gene library, which was paired with the knocked-in human-origin antibody heavy chain gene for antibody expression. ELISA was employed to screen for high-affinity chimeric antibodies. Amino acid changes in the light chain of high-affinity chimeric antibodies were analysed by comparing them with mouse-origin germline antibody light chain genes. Chimeric antibodies with single amino acid changes in the light chain were constructed and expressed, and their affinity and neutralization abilities were tested through ELISA and pseudovirus neutralization experiments. By comparing the affinity and neutralization abilities of the chimeric antibodies with or without single amino acid changes in the light chain, the key single amino acid change was analysed. Results ·Compared to unimmunized mice, the immunized mice showed an increased titer of specific antibodies against SARS-CoV-2 on the serum level, along with an elevated proportion of plasma cells and GC B cells in the spleen and lymph nodes. ELISA showed that a high-affinity chimeric antibody was screened from GC B cells in the mouse spleen. The light chain of the antibody had a 76th serine-to-isoleucine substitution and a 98th phenylalanine deletion. Another ELISA showed that the chimeric antibody exhibited high affinity, the antibody without amino acid change on the light chain and the antibody with only the 98th phenylalanine deletion showed low affinity, and the antibody with only the 76th serine-to-isoleucine substitution demonstrated intermediate affinity between the chimeric antibody and the antibody without amino acid change on the light chain. Pseudovirus neutralization experiments revealed that the chimeric antibody had a half-maximal inhibitory concentration (IC50) of 0.995 ng/μL; the antibody with only the 76th serine-to-isoleucine substitution had an IC50 of 1.724 ng/μL, indicating a slight decrease in neutralization ability; the antibody with only the 98th phenylalanine deletion had an IC50 of 71.05 ng/μL; the antibody without amino acid change on the light chain had an IC50 of 42.06 ng/μL, suggesting weak neutralization ability. Conclusion ·For the screened human-mouse chimeric antibodies that neutralize SARS-CoV-2 in this study, the key amino acid change determining the neutralization ability of the chimeric antibody is the 76th serine-to-isoleucine substitution.

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    Clinical research
    Comparison of long-term pregnancy outcomes between neosalpingostomy and salpingectomy for infertile women with bilateral severe hydrosalpinx
    YAN Li, WANG Yang, LIU Xiaoyi, PAN Yilian, ZHU Minjiao, LIU Jinglan, ZHANG Jian
    2023, 43 (6):  728-737. 
    doi: 10.3969/j.issn.1674-8115.2023.06.009

    Abstract ( 206 )   HTML ( 18 )   PDF (2596KB) ( 124 )  

    Objective ·To compare the pregnancy outcomes of infertile women with bilateral severe hydrosalpinx receiving neosalpingostomy or salpingectomy. Methods ·The single-center prospective cohort study from 2005 to 2012 focused on pregnancy outcomes of infertile women aged 20?40 years, with bilateral severe hydrosalpinx, undergoing bilateral neosalpingostomy or salpingectomy in International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University School of Medicine. The choice for treatment was based on a shared decision approach, and the participants were divided into the neosalpingostomy group and salpingectomy group. After registration of baseline characteristics, including age, birth place, reproductive history, preoperative hysterosalpingography results, surgical findings, and pregnancy outcomes, women were followed up on an annual basis until July 2020 for the occurrence of live birth by outpatient follow-up or telephone questionnaire. Intention-to-treat analysis and per-protocol analysis were applied to compare the pregnancy outcomes. Kaplan-Meier analysis and COX proportional hazard model were used to analyze the reproductive outcomes. In addition, subgroup analysis was performed based on age stratification. The main outcome measures were live birth rate, cumulative live birth rate, and factors affecting live birth. Secondary outcome measures included the mode of conception, time to live birth, biochemical pregnancy rate, clinical miscarriage rate, and ectopic pregnancy rate. Results ·A total of 113 women were included in the analysis, 58 women underwent bilateral neosalpingostomy, and 55 women underwent bilateral salpingectomy. The study demonstrated that in infertile women with bilateral severe hydrosalpinx, bilateral salpingectomy achieved higher cumulative live birth rate than bilateral neosalpingostomy (76.36% vs 62.07, HR=2.18,95%CI 1.37?3.45). In the neosalpingostomy group, 34.48% (20/58) live births were obtained after in vitro fertilization treatment, and 27.59% (16/58) live births were obtained through spontaneous conception which mainly occurred within 3 years after initial neosalpingostomy, while all live births in the salpingectomy group were obtained after assisted reproductive therapy. However, the risk of ectopic pregnancy was higher in the neosalpingostomy group than that in the salpingectomy group (20.69% vs 1.82%, P<0.001). No statistically significant differences regarding biochemical pregnancy and clinical miscarriage between the two groups were found. During the subgroup analysis, the cumulative live birth rate of the salpingectomy group (n=51) was significantly higher than that of the neosalpingostomy group (n=48) in women younger than 35 years old (HR=2.25, 95%CI 1.39?3.66), while between two groups of women aged 35 years old or older, there was no statistically significant difference in the cumulative live birth rate (HR=1.60, 95%CI 0.36?7.19). In addition, after adjustment for confounding factors including age, previous abortion history, fibroid, benign ovarian cyst, and endometriosis, COX proportional hazard analysis revealed that salpingectomy was positively correlated to live birth compared with neosalpingostomy (aHR=1.94, 95%CI 1.18?3.18). Conclusion ·For infertile women with bilateral severe hydrosalpinx, neosalpingostomy provides the possibility for spontaneous conception but also brings about certain risk of ectopic pregnancy. Bilateral salpingectomy can achieve higher cumulative live birth rate while receiving postoperative in vitro fertilization treatment.

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    Behavioral and eye movement study of attention bias to alcohol-related cues in male alcohol-dependent patients and correlation analysis of psychological factors
    SI Yuqi, LUO Ruyan, CHEN Tianzhen, WANG Lihui, ZHONG Na, JIANG Haifeng, ZHAO Min
    2023, 43 (6):  738-746. 
    doi: 10.3969/j.issn.1674-8115.2023.06.010

    Abstract ( 227 )   HTML ( 17 )   PDF (1611KB) ( 249 )  

    Objective ·To investigate if male alcohol-dependent patients have attention bias to alcohol-related pictures, show the behavioral and eye movement characteristics of attention bias, and explore the correlation between attention bias and sleep, anxiety, depression, impulsion and other psychological factors. Methods ·Twenty-nine subjects in the case group (alcohol-dependent patients who were hospitalized in Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, from August 2021 to February 2022) and 29 healthy subjects in the healthy control group participated in the study. The experimental design was a mixed experimental design of three-factor hybrid. The cue types were alcohol-related and emotion pictures. The probe was on the same side or on the opposite side of the alcohol or emotional picture. The characteristics of subjects' attentional bias to alcohol cues were investigated by using the classical dot detection paradigm and eye movement monitoring technique. Groups were inter-group variables, and clue types and relative locations of probe points were intra-group variables. The behavioral and eye movement data were collected while the study subjects viewed pairs of alcohol-related and neutral pictures, or pairs of emotional and neutral pictures in a dot-probe paradigm. Dependent variables included behavioral indicators and eye movement indicators. Pittsburgh Sleep Quality Index (PSQI), 7-tiem Generalized Anxiety Disorder Scale (GAD-7), Patien Health Questionnaire (PHQ-9), and Barratt Impulsiveness Scale (BIS-11) scales were used to assess psychosomatic conditions such as sleep, anxiety, depression, and impulsivity, respectively. Behavioral and eye movement characteristics of attention bias in the alcohol-dependent group were analyzed. In addition, the correlation with behavioral and eye movement characteristics of attention bias and scale scores was analyzed. Results ·The behavioral results showed that the reaction time of the alcohol-dependent group was significantly longer than that of the healthy control group (P=0.006). The eye movement results showed that when the type of cue was alcohol-related picture, the alcohol-dependent group had slower attention detection (P=0.031) and longer attention maintenance (P=0.005) on alcohol-related cues. Moreover, the pupil size during the viewing of alcohol-related cues (P=0.001) and emotional cues (P=0.008) were significantly smaller than those of the healthy control group. It was also found that, there was a negative correlation between the correct rate of the alcohol-dependent group and the BIS-11 scale score (r=-0.437, P=0.032), and a positive correlation between reaction time and GAD-7 score (r=0.407, P=0.033). The time of the first visual fixation entry was positively correlated with GAD-7 score (r=0.414, P=0.045), and the PSQI score was positively correlated with PHQ-9 score (r=0.422, P=0.041) in the case group. Conclusion ·Alcohol-dependent patients have attention bias towards alcohol-related cues according to the behavioral and eye movement result. Compared with the traditional behavioral regression of attention bias based on correct rate and reaction time results, eye movement provides more direct and multi indicator evidence for the evaluation of attention bias in alcohol-dependent patients.

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    Construction and validation of prognostic risk model for hepatocellular carcinoma based on biological analysis of palmitoyl-associated enzyme long-chain non-coding RNA
    YU Li, SU Xiandu, ZHANG Min, LI Yahui, WANG Le
    2023, 43 (6):  747-754. 
    doi: 10.3969/j.issn.1674-8115.2023.06.011

    Abstract ( 159 )   HTML ( 23 )   PDF (4673KB) ( 185 )  

    Objective ·To explore the effect of screening the expression of long non-coding RNA (lncRNA) related to palmitoylation on prognosis of liver cancer based on The Cancer Genome Atlas (TCGA) database and construct a risk prediction model in liver cancer. Methods ·The sequencing data and the corresponding clinical information of 374 liver cancer tissues and 50 normal tissue samples were downloaded from TCGA database. The differential zinc finger aspartate-histidine-histidine-cysteine domain (ZDHHC) between liver cancer tissues and normal tissues was used to construct the expression profile of lncRNA related to ZDHHC. Furthermore, the prediction model was constructed by LASSO regression algorithm and the validity of the model prediction was verified to analyze the relationship between high-risk and low-risk groups and immune function and to predict the response to immunotherapy. Results ·There were 20 differentially expressed ZDHHCs in hepatocellular carcinoma, among which 656 lncRNAs were correlated with differential ZDHHCs (all P<0.05). Univariate COX analysis showed that 22 lncRNAs were associated with the prognosis of hepatocellular carcinoma (HR 1.47?13.05, all P<0.05), and LASSO regression analysis included 3 lncRNAs to construct a risk model. The risk score=0.662 6×AC026356.1+0.213 9×AC026401.3+0.405 6×POLH-AS1. In the model, the overall survival (OS) and progression-free survival (PFS) of patients in the high-risk group were significantly lower than those in the low-risk group (all P<0.05). Multivariate COX regression analysis showed that the model as a risk factor was an independent factor affecting survival (HR=1.375, 95%CI 1.208?1.566). In the risk model, there were significant differences between high-risk and low-risk immune function pathways, and the response level of high-risk patients to immunotherapy was lower (P<0.05). Conclusion ·The use of a risk model based on palm acylation related lncRNA expression can independently predict the survival period of liver cancer patients, providing reference for patients receiving immunotherapy.

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    Review
    Research progress of integrated stress response in pathogenesis of Alzheimer's disease
    SUN Hui, JIN Hongfu, GUO Shenrui, FENG Yiyuan, YIN Yafu, WANG Hui, CHENG Weiwei
    2023, 43 (6):  755-760. 
    doi: 10.3969/j.issn.1674-8115.2023.06.012

    Abstract ( 292 )   HTML ( 25 )   PDF (1331KB) ( 235 )  

    Integrated stress response (ISR) is a cellular adaptive response induced by stress, which is strictly regulated by multiple phosphokinases, phosphatases and other proteins to maintain protein homeostasis. Studies have shown that ISR is abnormally activated in Alzheimer's disease, and targeted regulation of different proteins in ISR pathway inhibits the abnormal activation of ISR, leading to restoration of protein homeostasis and alleviation of the neuropathological changes and memory impairment in Alzheimer's disease models. These lines of evidence suggest that ISR has the potential to be a therapeutic target in Alzheimer's disease treatment. This paper reviews the abnormal activation and regulation mechanism of ISR in Alzheimer's disease and discusses the application of ISR as therapeutic targets to Alzheimer's disease models.

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    Research progress in the relationship between mitochondrial dysfunction and osteoporosis
    JIN Fangquan, FAN Chenghu, TANG Xiaodong, CHEN Yantong, QI Bingxian
    2023, 43 (6):  761-767. 
    doi: 10.3969/j.issn.1674-8115.2023.06.013

    Abstract ( 424 )   HTML ( 39 )   PDF (1922KB) ( 389 )  

    Osteoporosis (OP) is a chronic senile bone disease characterized by decreased bone mass and increased bone fragility. There are many inducing factors and the pathogenesis is complex. To explore the mechanism of OP and improve clinical efficacy has always been a hot topic in life science. In recent years, it has been found that mitochondria play an important role in the pathogenesis of OP. Functional abnormalities such as mitochondrial energy metabolism, mitochondrial oxidative stress, mitochondrial autophagy, mitochondrial-mediated apoptosis and mitochondrial dynamics can interfere with the differentiation of bone marrow mesenchymal stem cells through different signal pathways, cytokines and protein expression to regulate osteoblast activity, proliferation and differentiation, and start the process of osteoclast apoptosis. Therefore, taking mitochondria as the target, regulating the functions of mitochondrial energy metabolism, oxidative stress, autophagy and kinetics, inducing osteogenic differentiation of bone marrow mesenchymal stem cells, promoting osteoblast differentiation and mineralization, and inducing osteoclast apoptosis are potential strategies for the prevention and treatment of OP. In this article, the mechanism of mitochondrial dysfunction in OP was reviewed by referring to relevant literature at home and abroad, in order to lay a foundation for further research.

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    Research progress in biological activities and mechanisms of theabrownin
    WANG Jieyi, ZHENG Dan, ZHENG Xiaojiao, JIA Wei, ZHAO Aihua
    2023, 43 (6):  768-774. 
    doi: 10.3969/j.issn.1674-8115.2023.06.014

    Abstract ( 584 )   HTML ( 49 )   PDF (1358KB) ( 589 )  

    Tea is beneficial to human health, which is rich in tea pigments with important biological activities. Theabrownin, derived from theaflavins and thearubigins by oxidative polymerization, mainly distributes in semi-fermented oolong tea, and completely fermented black tea and dark tea. As a kind of macromolecular substance, theabrownin cannot be directly absorbed by the gut, but it can directly interact with intestinal microbiota to regulate and maintain the homeostasis of intestinal flora. Theabrownin has multiple physiological roles via modulating the gut microbiota, including inhibiting hepatic cholesterol production, promoting the catabolism of cholesterol and triglyceride, and promoting energy metabolism in adipose tissues, thereby improving lipid metabolism. Theabrownin can also directly influence the gut absorption of glucose to improve carbohydrate metabolism and maintain blood glucose homeostasis. Theabrownin plays an anti-tumor role by inducing apoptosis and regulating gene expression in tumor cells. Theabrownin also plays an anti-inflammatory role via participating in the regulation of the immune cell differentiation and the levels of inflammatory factors. This review summarizes the formation process, the extraction procedures, and the chemical structure of theabrownin, and reviews the effects and mechanisms of theabrownin on intestinal microbiota, lipid metabolism, blood glucose homeostasis, cancer and inflammation.

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    Research progress in autologous regeneration of human corneal endothelial cells
    CHEN Jin, FU Yao
    2023, 43 (6):  775-780. 
    doi: 10.3969/j.issn.1674-8115.2023.06.015

    Abstract ( 271 )   HTML ( 20 )   PDF (1350KB) ( 452 )  

    Human corneal endothelial cells (HCECs) are very important for maintaining corneal transparency, but HCECs remain arrested at the G1 phase after embryonic development and could not proliferate and regenerate in vivo. The density of HCECs decreases spontaneously with corneal development and aging, while systemic factors and corneal diseases can further cause a massive loss to HCECs, lead to corneal opacity and edema and ultimately induce vision impairment. Therefore, the regeneration of HCECs has always been a heated topic in the field of corneal endothelial research. Currently, function restoration of exogenous corneal endothelium mediated by cell therapy and autologous regeneration of endogenous HCECs have made amazing breakthroughs, with endogenous HCECs autologous regeneration being a more convenient and physiological treatment option. This review summarizes and analyzes the strategies and related techniques that are currently applied to the autologous regeneration of HCECs in aspects of operative treatment, gene therapy and pharmacological treatment.

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    Advances in the application of 18F-FDG PET/CT radiomics for diagnosis, treatment and prognosis prediction of lymphoma
    CHENG Ran, HU Jiajia, LI Biao
    2023, 43 (6):  781-787. 
    doi: 10.3969/j.issn.1674-8115.2023.06.016

    Abstract ( 312 )   HTML ( 24 )   PDF (1313KB) ( 290 )  

    Lymphoma is a highly heterogeneous hematological malignancy that can affect multiple organs throughout the body, exhibiting significant clinical variations among its subtypes. 18F-fluorodeoxyglucose (18F-FDG) PET/CT plays a crucial role in the clinical diagnosis and treatment of lymphoma by facilitating anatomical localization and quantification of metabolic characteristics of highly aggressive lymphomas. This imaging examination method enables a comprehensive evaluation by comparing the metabolic changes before and after treatment, as well as the metabolic difference between lesions and blood pools. However, the heterogeneity of lymphoma, coupled with the limitations of 18F-FDG PET/CT in differentiation, poses challenges for physicians and adversely impacts the clinical treatment plan and prognosis of patients. With the advancement of computer hardware and image analysis technology, radiomics technology, based on the extraction of imaging features of lesions for analysis and diagnosis, has emerged. Numerous researchers have dedicated their efforts to exploring imageomics in lymphoma assessment by using 18F-FDG PET/CT. By integrating feature data with relevant clinical information, models have been developed to effectively correlate image information, clinical data, pathology, and survival outcomes, thereby enhancing the accuracy and efficiency of imaging diagnosis. Furthermore, the utilization of predictive models for prognosis and treatment efficacy has the potential to mitigate subjective errors arising from disparities in physician experience, thereby contributing to the realization of personalized medicine. This review intends to comprehensively summarize the research progress of 18F-FDG PET/CT radiomics in the diagnosis, treatment and evaluation of lymphoma in recent years, from the aspects of diagnosis and differential diagnosis, prognosis prediction and risk grading, drug efficacy prediction and radiomics analysis algorithm optimization, so as to provide insights for future research in machine learning and the development of medical imaging analysis techniques.

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    Research progress in the effect of nutritional intervention on cognitive impairment related to Alzheimer's disease
    JIANG Xinting, HUANG Gaozhong
    2023, 43 (6):  788-794. 
    doi: 10.3969/j.issn.1674-8115.2023.06.017

    Abstract ( 354 )   HTML ( 29 )   PDF (1288KB) ( 280 )  

    Alzheimer's disease (AD) is an age-related neurodegenerative disease with insidious onset and slow progression. The progression of AD from only brain pathological changes to clinically identifiable cognitive changes is affected by a variety of environmental factors inside and outside the organism and can last for decades. Cognitive impairment is an important clinical feature of AD that impairs the quality of life of the elderly in their later years, and the available drugs for the treatment of AD have failed to cure the disease, indicating the importance of early prevention of AD-related cognitive impairment. Most current research on the relationship between nutrition and AD takes nutritional intervention as a preventive method for AD-related cognitive impairment. The role of dietary supplement or restriction on AD-related cognitive impairment is related to multiple pathways. It is worth noting that the gut microbiome, as an important medium in the effect of dietary on the host, can influence cognitive function through the "microbial-gut-brain axis". The antioxidant and anti-inflammatory properties of some foods are beneficial for improving cognitive function. In this paper, relevant studies in recent years were analyzed to discuss the effects of certain single nutrients (vitamins, polyphenols, and long chain polyunsaturated fatty acids) and overall nutritional patterns (Mediterranean diet, dietary approaches to stop hypertension diet, Mediterranean-DASH intervention for neurodegenerative delay, and ketogenic diet) on cognitive function, so as to provide ideas and reference for the prevention and treatment of AD-related cognitive impairment.

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