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    Analysis of clinical trial research in Shanghai Jiao Tong University School of Medicine
    PENG Shutao, QIU Xiaochun
    2022, 42 (8):  971-979. 
    doi: 10.3969/j.issn.1674-8115.2022.08.001

    Abstract ( 84 )   HTML ( 223 )   PDF (4893KB) ( 412 )  

    Objective ·To analyze the discipline distribution, research teams, multi-center cooperation and trend of clinical trial registration and published papers of Shanghai Jiao Tong University School of Medicine (SJTUSM) from 2012 to 2021. Methods ·On the Dimensions, and China and US clinical trial registration platforms, the clinical trial information registered by the institutions affiliated to SJTUSM from 2012 to 2021 was retrieved. Each clinical trial was classified and marked according to the classification standards such as Health Research Classification System (HRCS) and International Commission on Radiological Protection (ICRP). Clinical trial papers published by the first author or corresponding author from SJTUSM in the same period were retrieved in PubMed. EXCEL 2016 and VOSviewer 1.6.18 software were used to conduct cluster analysis and visual summary. Results ·From 2012 to 2021, Chinese researchers participated in 54 652 newly registered clinical trials worldwide, accounting for 13.63% of the global in total. Beijing, Shanghai and Guangzhou have been the top three cities with the most clinical trials in China. The number of newly registered and underdeveloped clinical trial projects in SJTUSM has been basically increased year by year in the past 10 years, but it declined slightly in 2021. In total, 3 970 clinical trials were registered by SJTUSM, in which 44.4% were registered on the Chinese clinical trial platform and 55.0% were registered on the US clinical trial platform, and 85.5% were initiated by researchers. Cancer, cardiovascular disease, oral and gastrointestinal disease, mental disease, and metabolic and endocrine disease were the major areas of clinical trial research of SJTUSM. Lung cancer research ranked the first in all 47 kinds of tumor research. The Sixth People 's Hospital, Ruijin Hospital and Renji Hospital ranked top 3 in clinical trial registration among hospitals affiliated to SJTUSM. A total of 1 898 papers (5.4%) were published in clinical trials with SJTUSM as the first author 's or correspondent author 's institution, and the research topics were mainly distributed in the fields of gastroenterology, heart disease, tumor, radiation, orthodontics and diabetes. The affiliated hospitals of Fudan University has been the main institutions of clinical trial cooperation. SJTUSM has formed core research teams in the fields of diabetes, hypertension, orthopedics, radiology and nephrology. Conclusion ·SJTUSM has obvious advantages in clinical trial research discipline and a great potential for emerging disciplines. Innovative clinical research teams have been formed in SJTUSM. Multi-center clinical trials are the norm of clinical trials, and SJTUSM has presided over international multi-center clinical trial cooperation in some fields. However, compared with the clinical trial registration in the world and other domestic regions in 2021, the number of clinical trial registrations of SJTUSM has decreased significantly, and the reasons need to be further analyzed.

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    Comparison of mitochondria and NAD+ level in the murine cochleae of C57BL/6J mice at different ages
    FENG Baoyi, DONG Tingting, ZHENG Xiaofei, TAO Yong, WU Hao
    2022, 42 (8):  980-986. 
    doi: 10.3969/j.issn.1674-8115.2022.08.002

    Abstract ( 96 )   HTML ( 30 )   PDF (3503KB) ( 402 )  

    Objective ·To investigate the changes of mitochondria and nicotinamide adenine dinucleotide (NAD+) levels in the cochleae of C57BL/6J mice at different ages, and explore potential mechanism of age-related hearing loss. Methods ·Forty C57BL/6J male mice aged 1, 4, 8, 12 months, respectively, were chosen and classified into 4 groups in terms of age (n=10). Auditory brain response (ABR) and distortion product otoacoustic emission (DPOAE) were conducted to detect the auditory function of mice at different ages; real-time quantitative PCR (RT-qPCR) was applied to compare the mRNA expression levels of the genes associated with mitochondrial energy metabolism in the cochleae of mice at different ages, including Ndufb5 (NADH: ubiquinone oxidoreductase subunit B5), Sdha (succinate dehydrogenase complex flavoprotein subunit A), Sdhc (succinate dehydrogenase complex subunit C), and Atp5b (ATP synthase, H+ transporting mitochondrial F1 complex, beta subunit); the changes of mitochondrial quantity in the cochlear hair cells from the mice aged 1 month and 12 months were observed by whole-mount immunofluorescence; the mitochondrial ultrastructure in the cochlear sensory epithelia including outer and inner hair cells, myelinate nerve fibers and spiral ganglion neurons of 1- and 12-month-old mice was observed by transmission electron microscope (TEM); NAD+ levels in the cochleae of mice at different ages were detected by quantitative colorimetry. Results ·The ABR thresholds of the 12-month-old mice were significantly elevated in comparison with those of the 1-month-old mice at the frequency range of 5.66?45.00 kHz (P<0.01); and the DPOAE thresholds of the 12-month-old mice were significantly elevated in comparison with those of the 1-month-old mice at the frequency range of 11.32?32.00 kHz (P<0.01). The expression levels of the genes related to mitochondrial functions including Ndufb5, Sdha, Sdhc, and Atp5b showed a downward trend with the age, which in the 8-month-old and 12-month-old mice were significantly different from those in the 1-month-old mice (P<0.05). Immunostaining showed that the number of mitochondria in cochlear inner hair cells of the 12-month-old mice was significantly lower than that of 1-month-old mice. It was observed by TEM that vacuolar degenerated mitochondria and larger lipofuscin existed in the inner hair cells, myelinate nerve fibers and spiral ganglion neurons of the 12-month-old mice. The NAD+ level showed a decreasing trend with age, declining significantly from 8 months of age, compared with the 1-month-old mice (P<0.01). Conclusion ·Mitochondrial dysfunction with abnormal structure and descending NAD+ levels in the cochleae is consistent with hearing function deterioration in C57BL/6J aging mice.

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    Preliminary study on the cellular level of SARS-CoV-2 proteins mediated by macropinocytosis pathway
    JIANG Gan, YANG Yuquan, CHEN Yaoxing, HOU Zhaoyuan, GAO Xiaoling, CHEN Hongzhuan, JIA Hao
    2022, 42 (8):  987-996. 
    doi: 10.3969/j.issn.1674-8115.2022.08.003

    Abstract ( 75 )   HTML ( 9 )   PDF (8168KB) ( 425 )  

    Objective ·To investigate the effects of several key proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on macropinocytosis in various cell models. Methods ·① The interactions between spike protein receptor-binding domain (S-RBD), nucleocapsid protein (N) and non-structural protein-7 (NSP7) of SARS-COV-2 and HEK-293T intracellular proteins were explored by co-immunoprecipitation assay. ② In vitro, S-RBD, N and NSP7 proteins of SARS-CoV-2 were incubated with HEK-293T/bEnd.3/Beas-2b cells (normal cell models), respectively, and the changes of macropinocytosis level of cells labeled with fluorescein isothiocyanate (FITC)-70 kDa-dextran were observed. ③ In vitro, S-RBD, N and NSP7 proteins of SARS-CoV-2 were incubated with inflammatory cells induced by lipopolysaccharide (LPS), respectively, and the changes of macropinocytosis level of inflammatory cells were analyzed. ④ In the normal cell models and inflammatory cell model, EIPA or lipoprotein nano-drug carriers loaded with Rab5 small interfering RNA (siRNA) were used to inhibit the macropinocytosis induced by SARS-CoV-2 proteins, respectively, and the uptake of S-RBD, N and NSP7 proteins by cells were further observed. Results ·① The three proteins of SARS-COV-2 could bind to Rab small GTPase proteins after being absorbed into cells. ② It was found that S-RBD, N and NSP7 proteins of SARS-COV-2 could induce the macropinocytosis after entering the HEK-293T/bEnd.3/Beas-2b cells. ③ Furthermore, the three proteins of SARS-COV-2 could enhance the megapinocytosis of the inflammatory cell. ④ After treatment with EIPA (75 μmol/L) or lipoprotein nano-drug carriers loaded with Rab5 siRNA, the uptake of S-RBD, N and NSP7 proteins were decreased in both types of cells. Conclusion ·S-RBD, N and NSP7 proteins of SARS-CoV-2 can up-regulate megapinocytosis levels in various cell models, especially in the case of combined inflammation infection. At the same time, macropinocytosis inhibitor / lipoprotein nano-drug carrier can inhibit the macropinocytosis up-regulated by the above proteins, and then reduce the entry levels of viral proteins.

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    Basic research
    Marine sponge-derived smenospongine overcomes resistance of cisplatin via inhibiting EGFR-Akt-ABCG2 pathway in NSCLC cells
    LIAO Yahui, LIU Liyun, ZHU Hongrui, LIN Houwen, YAN Jizhou, SUN Fan
    2022, 42 (8):  997-1007. 
    doi: 10.3969/j.issn.1674-8115.2022.08.004

    Abstract ( 82 )   HTML ( 10 )   PDF (4930KB) ( 417 )  

    Objective ·To explore the antitumor activities and mechanisms of the sesquiterpene amine quinone compound smenospongine (SME) in non-small cell lung cancer (NSCLC) cell line A549 and cisplatin-resistant cell line A549/DDP. Methods ·Parental cell A549 and its cisplatin-resistant cell A549/DDP were used as research models. CCK-8 assay was used to detect the half maximum inhibitory concentration (IC50) of the two cell lines treated with first-line chemotherapeutic drugs, in order to verify the multidrug resistance of A549/DDP. Colony formation assay was used to detect the effect of SME on the proliferation of parental and drug-resistant cells. Transwell invasion assay and Western blotting were used to detect the effect of SME on epithelial to mesenchymal transformation (EMT) of A549/DDP; Western blotting and quantitative real-time PCR (qRT-PCR) were used to detect the protein and mRNA expression levels of multidrug resistance genes regulated by SME in two cell lines and the molecular mechanism of drug resistance. Furthermore, Western blotting was used to detect the effect of SME on the upstream protein of multidrug resistance protein, ATP-binding cassette superfamily G member 2 (ABCG2), and flow cytometry was used to detect the effect of SME on the cell cycle of parental and cisplatin-resistant cells. TdT-mediated dUTP Nick-end labeling (TUNEL) and Western blotting were used to detect the effect of SME on apoptosis of the two cell lines. Results ·Compared with parental cells, cisplatin-resistant A549/DDP cells showed significant resistance to cisplatin and showed multidrug resistance to the first-line chemotherapy drugs used on lung cancer. SME markedly inhibited the proliferation and clone formation of A549 and A549/DDP as well as the EMT of drug-resistant cell. SME notably down-regulated the expression of ABCG2 protein and mRNA, and inhibited the epidermal growth factor receptor (EGFR)-serine/threonine kinase (Akt) signal pathway upstream of ABCG2, which thereby down-regulated ABCG2, and positively regulated FoxO1. SME induced G0/G1 arrest and induced apoptosis of both cells. Conclusion ·As a new small molecular compound in overcoming the drug resistance of NSCLC, SME inhibits the cell viability of A549 and A549/DDP by restraining EGFR-Akt signal pathway which thereby down-regulates ABCG2, positively regulates FoxO1 and inhibits EMT of A549/DDP, which finally leads to apoptosis.

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    Study on Prrx1+ periodontal ligament stem cells during orthodontic tooth movement by lineage tracing
    WANG Xijun, JIN Anting, HUANG Xiangru, XU Hongyuan, GAO Xin, YANG Yiling, DAI Qinggang, JIANG Lingyong
    2022, 42 (8):  1008-1015. 
    doi: 10.3969/j.issn.1674-8115.2022.08.005

    Abstract ( 82 )   HTML ( 10 )   PDF (4046KB) ( 478 )  

    Objective ·To investigate the dynamic distribution of paired related homebox 1 (Prrx1) positive cell lineage (Prrx1+ cell lineage) in periodontal ligament stem cells (PDLSCs) during tooth movement in mice by Cre/loxP recombination system. Methods ·By using Cre/loxP recombination system, inducible Prrx1-CreERT2mice were mated with R26tdTomato fluorescently labeledmice, and their offspring mice were genotyped by PCR. Eight offspring mice were injected with tamoxifen (TA) intraperitoneally to mark the Prrx1+cell lineage (tdTomato+ cells) in PDLSCs. The orthodontics tooth movement (OTM) model was constructed by placing a force-loading device on the left side of maxilla (i.e., OTM side), and the right side without force was control side (i.e., Ctrl side). The mice were sacrificed on the third day (OTM 3 d) and the seventh day (OTM 7 d) of tooth movement, and their bilateral maxillary molars and surrounding periodontium were collected, decalcified, embedded and frozen sectioned. The changes of periodontal ligament in the tension area and compression area were observed by hematoxylin-eosin staining (H-E staining), and the dynamic distribution of Prrx1+ celllineage was observed by immunofluorescence staining. Results ·The genotype of the offspring mice was identified by PCR as Prrx1-CreERT2;R26tdTomato . With the increased action of the stressing device, the tooth movement distance of OTM 7 d mice [(87.44±4.02) μm] increased significantly compared with that of the OTM 3 d mice [(42.81±5.04) μm], suggesting OTM model was successfully constructed. H-E staining showed that the periodontal ligament and its gap in the compression area of the OTM side was compressed and narrowed on OTM 3 d, and its width was gradually restored on OTM 7 d; the periodontal ligament in the tension area of the OTM side was stretched on OTM 3 d, and the periodontal ligament was more regularly arranged on OTM 7 d than that on OTM 3 d. Immunofluorescence staining showed that the number of tdTomato+ cells in the periodontal ligament of the compression area on the OTM side was lower than that of the Ctrl side on OTM 3 d, and the number of tdTomato+ cells in compression area on the OTM side was higher than that of the Ctrl side on OTM 7 d (both P<0.05); on both OTM 3 d and OTM 7 d, the number of tdTomato+ cells in tension area on the OTM side increased compared with that on the Ctrl side (both P<0.05). Conclusion ·The OTM model of Prrx1-CreERT2;R26tdTomato mice is successfully constructed, and the involvement of Prrx1+ cell lineage in periodontal remodeling during OTM is tentatively confirmed.

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    Effects and mechanisms of KRAS4AG12C and KRAS4BG12C in the proliferation and migration of human pulmonary epithelial cells
    ZOU Jinghua, GONG Miaomiao, SHEN Ying
    2022, 42 (8):  1016-1023. 
    doi: 10.3969/j.issn.1674-8115.2022.08.006

    Abstract ( 57 )   HTML ( 11 )   PDF (4296KB) ( 42 )  

    Objective ·To explore how the two splice variants of oncogenic mutant KRASG12C, KRAS4AG12C and KRAS4BG12C, promote the proliferation and migration of human pulmonary epithelial bronchial BEAS-2B cells. Methods ·The two splice variants of oncogenic mutant KRASG12C, KRAS4AG12C and KRAS4BG12C, were stably overexpressed in human normal pulmonary epithelial bronchial BEAS-2B cells by lentivirus packaging and infection system. Western blotting was used to verify whether the model was constructed successfully. Cell morphology was investigated by inverted phase-contrast microscopy. Cell proliferation was observed by the Incucyte Live Cell Analysis System. Cell migration was characterized by scratch wound assay and transwell assay. To investigate the mechanisms, RNA-sequencing (RNA-seq) was used to provide insight into the transcriptome of the indicated cells, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were performed to identify differential genes and signaling pathways enriched in ranked gene lists, and quantitative real-time PCR (qPCR) was used to further verify different genes. Student's t test (t test) was used for comparison between the two groups. Statistical significance was accepted at a value of P<0.05. Results ·Both overexpression of KRAS4AG12C and KRAS4BG12C induced morphological changes, including increased invasive pseudopodia structures and cell junctions of BEAS-2B cells. Compared with BEAS-2B cells, the cell proliferation was significantly enhanced in BEAS-2B KRAS4AG12C and BEAS-2B KRAS4BG12C cells. In addition, overexpression of KRAS4BG12C effectively promoted wound healing of BEAS-2B cells (P=0.000) and BEAS-2B KRAS4AG12C cells (P=0.006), as scratch wound assay characterized. And overexpression of KRAS4BG12C effectively promoted cell migration of BEAS-2B cells (P=0.033) and BEAS-2B KRAS4AG12C cells (P=0.048), as transwell assay characterized. Mechanically, compared with BEAS-2B KRAS4AG12C cells, cell adhesion molecules gene set was enriched and the mRNA levels of claudin 1 (CLDN1) (P=0.000) and cell adhesion molecule 3 (CADM3) (P=0.000) were up-regulated in BEAS-2B KRAS4BG12C cells. Conclusion ·This research first reports the differences between KRAS4AG12C and KRAS4BG12C in promoting BEAS-2B cells proliferation and migration, and the underlying mechanism. The oncogenic mutant KRAS4BG12C drives cell migration more significantly than KRAS4AG12C does, which may be related to the expression level of CLDN1 and CADM3. Our study provides insights for the design of KRAS-specific targeting inhibitors and individualized therapy for non-small cell lung carcinoma patients harboring KRAS4AG12C and KRAS4BG12C.

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    Study of the regulatory network of MUC1 and tumor-associated proteins
    CHU Yunkai, LIAO Chunhua, DENG Huayun, HUANG Lei
    2022, 42 (8):  1024-1033. 
    doi: 10.3969/j.issn.1674-8115.2022.08.007

    Abstract ( 69 )   HTML ( 9 )   PDF (5322KB) ( 20 )  

    Objective ·To investigate the level of the expression of mucin 1 (MUC1) in different cancers and its impact on patient survival, and predict the possible mechanisms of MUC1 involvement in oncogenesis and tumor progression by analyzing the regulatory network of tumor-associated proteins that interact with MUC1. Methods ·The mRNA levels of MUC1 in 33 tumors and the relationship between the expression of MUC1 and patient survival were analyzed by using the GEPIA 2 online platform. MUC1-HA plasmids were transfected in HEK293T cells, and then MUC1-binding proteins were obtained by co-immunoprecipitation (Co-IP) experiments with HA antibody, which was later analyzed by liquid chromatography-tandem mass spectrometry (LCMS/MS). The subcellular localization, molecular function, diseases involved, biological process of MUC1-binding proteins and the regulatory network of interactions between these proteins were analyzed by using String 11.5 online platform. Results ·MUC1 was highly expressed in 9 kinds of tumors, including breast cancer, cervical cancer, diffuse large B-cell tumor, glioblastoma multiforme, brain lower grade glioma, ovarian carcinoma, pancreatic carcinoma, thymoma, and uterine corpus carcinoma. The relationship between MUC1 expression and overall survival in these 9 kinds of tumors was analyzed, and MUC1 expression was found to be negatively correlated with the overall survival. Higher MUC1 expression was related to significantly shorter survival time in 6 kinds of tumors, including breast cancer, cervical cancer, glioblastoma multiforme, brain lower grade glioma, pancreatic carcinoma, and thymoma. A total of 526 MUC1-binding proteins were detected by mass spectrometry analysis, and these proteins were mostly localized in organelles, cytoplasm, and membrane structures. The main molecular functions of these proteins included protein binding, ion binding, and enzymatic activity. They were primarily involved in anatomical entity diseases, cell proliferation diseases, metabolic diseases, and cancers. The related biological processes largely consisted of cellular stress, metabolism, development, and biosynthesis. MUC1-binding proteins played various roles in signaling pathways of metabolism, cancer, cGMP-cGMP-dependent protein kinase (PKG), tumor necrosis factor (TNF), and cell cycle. Further analysis of MUC1-binding-protein-associated signaling pathways revealed that they were heavily implicated in cancer-related signaling pathways such as Wnt/β-catenin, Notch, and cAMP on the one hand, and promoted tumor development by regulating metabolism, apoptosis, and cell cycle on the other hand. Conclusion ·MUC1 is highly expressed in a variety of tumor issues and is associated with poor prognosis of patients. MUC1 regulates cellular metabolism and plays a part in tumor-related signaling pathways possibly through protein interactions. This study innovatively identifies several new MUC1-binding proteins, which lay the foundation for further investigation of new biological functions of MUC1.

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    Role of APOBEC3B in regulating replication stress of uveal melanoma
    ZONG Chunyan, HE Jie, ZHANG Zhe, JIA Renbing, SHEN Jianfeng
    2022, 42 (8):  1034-1044. 
    doi: 10.3969/j.issn.1674-8115.2022.08.008

    Abstract ( 70 )   HTML ( 11 )   PDF (4490KB) ( 11 )  

    Objective ·To explore the biological function of apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) in uveal melanoma (UM) and its impact on drug sensitivity. Methods ·The expression of APOBEC3B in ocular melanoma [UM and conjunctival melanoma (CM)] tissues and cell lines were verified by immunohistochemical staining and Western blotting, respectively. The association between APOBEC3B expression and prognosis in UM was analyzed by searching The Cancer Genome Atlas (TCGA) database. In order to construct the OMM2.3-APOBEC3B knockout cell line sgAPOBEC3B and control cell line Vector, the CRISPR-Cas9 plasmid APOBEC3B-sgRNA targeting APOBEC3B gene was designed. Colony formation assay was used to examine the effect of APOBEC3B knockout on OMM2.3 cell proliferation. At the same time, plasmid APOBEC3B-shRNA targeting APOBEC3B gene was designed to construct the OMM2.3-APOBEC3B knockdown cell line shAPOBEC3B and control cell line shCtrl. Differential genes of shAPOBEC3B and shCtrl cell line were detected by RNA sequencing (RNA-seq), the result of which was analyzed by gene set enrichment analysis (GSEA) in order to find the downstream pathways APOBEC3B involved in. Key downstream protein of downstream pathway was identified by immunofluorescence staining. Then targeted drugs of this pathway were applied to examine the effect of APOBEC3B on drug sensitivity in UM treatment. Results ·Immunohistochemical staining results showed that ocular melanoma (UM and CM) tissues had higher APOBEC3B expression than benign pigmented nevus tissues. Western blotting also showed that most ocular melanoma cells, including OMM2.3 cells, expressed higher levels of APOBEC3B compared to normal control cells, retinal pigment epithelium cells. Also, TCGA database analysis showed that UM patients with higher APOBEC3B expression had shorter overall survival (P=0.032) and disease-free survival (P=0.000). However, APOBEC3B knockout did not affect the colony formation ability of OMM2.3 cells, nor did APOBEC3B knockdown cause significant changes in the cell cycle. Differential gene enrichment analysis on the RNA-seq results of shAPOBEC3B and shCtrl cells showed that APOBEC3B regulated replication stress-related pathways in OMM2.3 cells. The heat map also showed that the gene expression of DNA replication stress-related pathways altered after APOBEC3B knockdown. Immunofluorescence staining showed that the level of phosphorylated replication protein A 32 kDa subunit (RPA32), a key target of replication stress pathway, was decreased after APOBEC3B knockdown. In drug sensitivity experiments on shAPOBEC3B and shCtrl OMM2.3 cells, it was found that OMM2.3 cells with APOBEC3B expression were more sensitive to cell cycle checkpoint kinase 1 (CHK1) inhibitor. Conclusion ·APOBEC3B is involved in regulating the replication stress-related pathways of OMM2.3 cells, and APOBEC3B-expressing OMM2.3 cells are more sensitive to the treatment of CHK1 inhibitor.

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    Association analysis of T cell receptor repertoire diversity with clinical characteristics and Fusobacterium nucleatum abundance in colorectal cancer patients
    HU Muni, JI Linhua, ZHANG Xinyu, SHEN Chaoqin, HONG Jie, CHEN Haoyan
    2022, 42 (8):  1045-1052. 
    doi: 10.3969/j.issn.1674-8115.2022.08.009

    Abstract ( 70 )   HTML ( 8 )   PDF (3477KB) ( 12 )  

    Objective ·To analyze the association between T cell receptor repertoire diversity in colorectal cancer (CRC) patients and clinical characteristics and Fusobacterium nucleatum (Fn) abundance. Methods ·Sixty-three surgical CRC specimens and adjacent normal mucosa tissues were collected from the Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine. Totally 53-paired qualified samples were subsequently sequenced on an Illumina HiSeq 4000 for paired-end 150 bp (PE150) sequencing. Quality control and genome annotation were carried out for the original sequencing data. Then a TRUST4 algorithm was further used to acquire TCR repertoire information from RNA sequencing results of tumor tissues and adjacent normal tissues. Meanwhile, the specific sequences of all samples' 16S rDNA were selected for high-throughput sequencing analysis. Clustered from the sequencing data after quality control, the operational taxonomic units (OTU) information was annotated based on rdp_16s_v16.fa taxonomic database to acquire bacterial abundance information, especially Fn. Immunarch R package was utilized to evaluate the characteristics of TCR repertoire clonotypes and diversity. Chao1 index, inverse Simpson index and Hill numerical curve were then conducted to assess the TCR repertoire diversity. Clinical features, such as gender, age, tumor location, and TNM stage, and biological factors like Fn load, were included to dichotomize patients into different groups, and repertoire diversity comparison between subgroups within different clinical features and Fn loads was conducted by Wilcoxon test subsequently. Results ·The number of TCR repertoire clonotypes in CRC tissues was lower compared to that in adjacent normal tissues (P=0.000). Chao1 index, inverse Simpson index and Hill number in tumor tissues were significantly lower than those in adjacent normal tissues (P=0.000). The Chao1 indexes, and inverse Simpson indexes between different gender, age (≥65 years vs <65 years) or TNM stage (Ⅰ/Ⅱ stage vs Ⅲ/Ⅳ stage) group showed no statistically significant difference (P>0.05). Tumors located in rectum had higher TCR clonotypes than those located in non-rectum (P=0.040). In addition, CRC patients with high Fn load demonstrated lower Chao1 indexes than those with low Fn load (P=0.030). Conclusion ·The TCR repertoire diversity is correlated with multiple clinical features as well as the abundance of Fn, indicating that the analysis based on TCR repertoire diversity of CRC patients can provide potential value for CRC tumorigenesis and development.

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    Clinical research
    Related factors and prognostic analysis of adverse events of immunotherapy in advanced gastric cancer
    HAN Ting, LÜ Chunxin, ZHUO Meng, XIA Qing, LIU Tengfei, WU Xiuqi, LIN Xiaolin, XIAO Xiuying
    2022, 42 (8):  1053-1061. 
    doi: 10.3969/j.issn.1674-8115.2022.08.010

    Abstract ( 68 )   HTML ( 13 )   PDF (2209KB) ( 97 )  

    Objective ·To explore the characteristics and predictive factors of immune-related adverse events (irAEs) in advanced gastric cancer patients treated with programmed death-1 (PD-1) inhibitors, and analyze the correlation between irAEs and prognosis. Methods ·A total of 140 patients with advanced gastric cancer treated with PD-1 inhibitors in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2018 to October 2021 were selected. They were divided into irAEs group and non-irAEs group according to whether they had irAEs or not. The clinical characteristics, irAEs occurrence and prognosis of the patients in the two groups were collected and analyzed. Multivariate Logistic regression model was used to analyze the related factors affecting the occurrence of irAEs, and the prediction model of irAEs was established. The receiver operating characteristic curve (ROC curve) was used to evaluate the ability of different indicators to predict the occurrence of irAEs. Kaplan-Meier survival curve was used to analyze the correlation between irAEs and prognosis. Cox proportional hazard model was used to analyze the related factors affecting the prognosis of patients. Results ·A total of 132 patients completed the follow-up, of which 63 patients (47.7%) developed irAEs. In the comparison of clinical characteristics between the groups, it was found that there were statistically significant differences in age≥65 years, Ki-67 index, leukocyte count, neutrophil count and regulatory T cell (Treg) count (all P<0.05). Multivariate Logistic regression analysis showed that Treg count was the protective factor for affecting the occurrence of irAEs (P=0.030). ROC curve showed that the combined index of Treg+Ki-67+Age (≥65 years) could better predict the occurrence of irAEs (AUC=0.753, 95% CI 0.623?0.848, P=0.000). Kaplan-Meier survival curve showed that the progression-free survival (PFS) of patients in the irAEs group was longer than that in the non-irAEs group (P=0.001). Cox proportional hazard regression analysis showed that irAEs was an independent influencing factor of PFS (P=0.006). Conclusion ·Treg count is an independent influencing factor for the occurrence of irAEs in patients with advanced gastric cancer undergoing PD-1 inhibitor immunotherapy, and its occurrence can prolong the PFS of patients. The combined index of Treg+Ki-67+Age (≥65 years) can better predict the occurrence of irAEs.

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    Feasibility of ultra-low-dose noncontrast CT based on deep learning image reconstruction to evaluate chest lesions
    ZHAO Keke, JIANG Beibei, ZHANG Lu, WANG Lingyun, ZHANG Yaping, XIE Xueqian
    2022, 42 (8):  1062-1069. 
    doi: 10.3969/j.issn.1674-8115.2022.08.011

    Abstract ( 79 )   HTML ( 12 )   PDF (2696KB) ( 82 )  

    Objective ·To explore the feasibility of using noncontrast ultra-low-dose CT (ULDCT) to evaluate chest target lesions based on response evaluation criteria in solid tumors (RECIST) and ground glass nodules (GGNs). Methods ·From April to June 2020, patients who underwent noncontrast chest ULDCT (0.07?0.14 mSv) and low-dose enhanced CT (2.38 mSv) and had measurable target lesions defined by RECIST and GGNs ≤1 cm in diameter were included. Four sets of CT images were reconstructed for each patient, including 3 sets of ULDCT images, i.e., adaptive statistical iterative reconstruction-V with an 80% strength level (ASIR-V-80%), deep learning image reconstruction of moderate strength (DLIR-M) and deep learning image reconstruction of high strength (DLIR-H), and one set of enhanced CT images as the reference. Results ·Eighty patients who had 80 target lesions and 27 GGNs met the inclusion criteria, and the average age was (62±11) years old. Between the ULDCT images (3 sets of image reconstruction) and enhanced CT, the measured values of target lesions (r=0.988, 0.987 and 0.990, respectively), GGNs≤1 cm in diameter (r=0.905, 0.906 and 0.969, respectively), mediastinal lymph node target lesions (r=0.969, 0.957 and 0.977, respectively), and hilar lymph node target lesions (r=0.972, 0.994 and 0.994, respectively) were highly correlated. Bland-Altman analysis showed that the difference between the measured size of lung target lesion and reference value in DLIR-H reconstruction image was 4.3% (95% limits of agreement: -5.7%?14.3%), and the difference between the measured size of mediastinal lymph node target lesion and reference value was 5.1% (-9.1%?19.3%), which was better than that of ASIR-V-80% [8.5% (-3.3%?20.3%), 9.7% (-6.0%?25.3%)] and DLIR-M [8.5% (-4.2%?21.3%), 8.8% (-9.9%?27.5%)]. The difference between the measured size of lymph node target lesions in DLIR-H images and the reference value was 18.3% (8.8%?27.9%), better than ASIR-V-80% [20.2% (-1.2%?41.5%)] and DLIR-M [23.4% (13.5%?33.2%)]. The difference between the measured size of GGNs in DLIR-H images and the reference value was 7.0% (-5.7%?19.7%), better than ASIR-V-80% [14.4% (-4.4%?33.2%)] and DLIR-M [16.3% (-4.1%?36.7%)]. Conclusion ·Noncontrast ULDCT based on DLIR-H is highly correlated and consistent with the traditional enhanced CT in evaluating chest target lesions and GGNs (≤1 cm in diameter), which is conducive to repeated scanning of tumors and GGNs at a significantly reduced radiation dose.

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    Value of combined perineural lymphovascular invasion and tumor-stroma ratio in guiding the prognosis of colorecatal cancer
    QIU Jiahui, CAI Qianqian, YANG Yan, CHENG Feichi, QIU Zhengjun, HUANG Chen
    2022, 42 (8):  1070-1080. 
    doi: 10.3969/j.issn.1674-8115.2022.08.012

    Abstract ( 76 )   HTML ( 8 )   PDF (2510KB) ( 16 )  

    Objective ·To explore the prognosis effects of tumor-stroma ratio(TSR), perineural invasion (PNI) and lymphovascular invasion (LVI) on patients with colorectal cancer (CRC). Methods ·Data of 948 patients diagnosed with CRC in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January 2014 to December 2018 were retrospectively analyzed, and according to pathological risk factors TSR, PNI and LVI, patients were divided into high risk group (n=81) and low risk group (n=867). After 1∶1 matching with SPSS software, 67 patients of the high risk group and 67 patients of the low risk group were obtained. The overall survival (OS) time was compared between patients in the high risk group and low risk group. The results were validated by using tissue microarray (TMA) dataset of 106 CRC patients from our research group. The clinical characteristics of the high risk group and low risk group were compared. Kaplan-Meier curve was used for survival analysis, and COX regression model was used to analyze the prognosis factors. Results ·Patients in the high risk group had a worse prognosis with a short median OS (27.7 months) than patients in the low risk group (31.1 months, P=0.000). The worse OS in patients with high risk group was validated in matched data and TMA dataset. Conclusion ·CRC with positive perineural lymphovascular invasion combined with high TSR is a type of CRC with poor prognosis, which can effectively make up for the defect of tumor-node-metastasis (TNM) stage in prognosis and can be used to predict postoperative disease development of CRC patients and guide treatment.

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    Three-dimensional finite element analysis on fiber-reinforced composite post-restored maxillary first molar with tooth defect
    ZHONG Qi, HUANG Yujie, ZHANG Yifan, SONG Yingshuang, WU Yaqin, QU Fang, HUANG Qingfeng, XU Chun
    2022, 42 (8):  1081-1094. 
    doi: 10.3969/j.issn.1674-8115.2022.08.013

    Abstract ( 70 )   HTML ( 9 )   PDF (7037KB) ( 15 )  

    Objective ·To explore the appropriate strategy for restoring maxillary first molars with palatal-occlusal (PO) defect or distal-occlusal (DO) defect by using fiber-reinforced composite posts. Methods ·Two types of defects in maxillary first molars were established: PO defect and DO defect. For each type, 5 finite element models with different restoration strategies were created: no post (NP), palatal post (PP), palatal and distobuccal posts (PDP), palatal and mesiobuccal posts (PMP), and palatal, distobuccal and mesiobuccal posts (PDMP). In the multi-post groups, if 2 posts overlapped in the resin core, the thinner one was horizontally trimmed 1 mm below the intersection point. The models were loaded by a vertical force—an 800 N force parallel to the long axis of the tooth, and a lateral force—a 225 N force directed at 45° to the long axis of the tooth. The following parameters were calculated by using finite element analysis: equivalent stress in the tooth structure and the posts, and maximum shear stress on the post-cement and cement-canal interfaces. Results ·Under the vertical loading, the maximal equivalent stress on the external surfaces of the tooth with PO defect was the lowest in the PMP group (36.17 MPa), while it was the lowest in the PDP group with DO defect (36.23 MPa). Under the lateral loading, it was the lowest in the PDMP group with PO defect (40.47 MPa), while it was the lowest in the PMP group with DO defect (42.05 MPa). With either defect, the equivalent stress on the internal surfaces generally decreased at the cervical 1/3 of root canals and increased at the middle 1/3 after post inserting. Palatal canal post and mesiobuccal canal post respectively withstood the highest equivalent stress under vertical loading and lateral loading (60.75?71.29 MPa and 45.91?51.82 MPa, respectively), and the maximal shear stresses on these two post-cement interfaces were also the highest under the corresponding loading (11.26?12.93 MPa and 12.38?13.03 MPa, respectively). The maximum shear stresses on the cement-canal interfaces were similar among the groups under the vertical loading (9.96?10.58 MPa), while under the lateral loading they were higher in the PMP group and the PDMP group. Conclusion ·The appropriate strategy for fiber-reinforced composite post restoration on maxillary first molars should be determined according to the type of tooth defect. For PO defect, the strategy of one post restoring in palatal canal is recommended; for DO defect, the strategy of two posts restoring in palatal and mesiobuccal canals respectively with approaches to reduce vertical occlusal force is recommended.

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    Preliminary exploration of diffusion-weighted imaging in pre-surgical planning of dermatofibrosarcoma protuberans
    LIU Siyu, WU Bing, LI Xiaomin, ZHAO Lulu, CHEN Jun, AI Songtao
    2022, 42 (8):  1095-1102. 
    doi: 10.3969/j.issn.1674-8115.2022.08.014

    Abstract ( 76 )   HTML ( 10 )   PDF (3127KB) ( 13 )  

    Objective ·To explore the value of diffusion-weighted imaging (DWI) in pre-surgical planning of dermatofibrosarcoma protuberans (DFSP). Methods ·The cases with DFSP in Shanghai Ninth People 's Hospital, Shanghai Jiao Tong University School of Medicine from May 2018 to March 2022 were enrolled. CT and MRI were conducted before surgery as a routine procedure. All the patients were randomly divided into MRI functional imaging group (CT plain scan and enhanced scan, MRI plain scan and enhanced scan, and DWI) and MRI conventional imaging group (CT plain scan and enhanced scan, and MRI plain scan and enhanced scan). The tumor boundaries of the two groups were outlined respectively by aligning CT with corresponding MRI images with computer- aided design software Medraw [alignment of CT images with DWI images in MRI functional imaging group and alignment of CT images with dynamic contrast-enhanced magnetic resonance imaging (DCE) images in MRI conventional imaging group] in order to complete the DFSP 3D tumor models and the 3D visualization reports, and to design surgical plans. The clinical characteristics of the two groups were completely collected. The recurrence rate and postoperative satisfaction evaluation of the two groups were compared. Results ·A total of 34 cases with DFSP having completed clinical and imaging information were enrolled in this research with an average age of (36.56±13.07) years. The tumor location of occurrence included 10 cases in the abdominal walls, 9 cases in the chest walls, 4 cases in the maxillofacial regions, 3 cases in the thighs, 3 cases in the shoulders, 2 cases in the hips, 2 cases in the waists, and 1 case in the feet. The average tumor diameter was (2.25±0.92) cm. Seventeen patients were included in the MRI functional imaging group and MRI conventional imaging group respectively with an average follow-up of (9.97±7.82) months. There were no significant differences in the basic clinical information between the two groups ( P>0.05). The recurrence rate of the MRI functional imaging group (0) was lower than that of the MRI conventional imaging group (29.4%), and the postoperative aesthetic satisfaction rate in the former group (100%) was higher than that in the latter group (70.6%). There were statistically significant differences in these results between the two groups ( P<0.05). Conclusion ·DWI is more advantageous for tumor boundary determination compared with conventional MRI; DWI-based preoperative image planning can reduce DFSP recurrence rate and improve aesthetics of the operative area to some extent.

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    Public health
    Associations between paraben exposure and pulmonary function in preschool children in Shanghai
    HU Yi, DING Guodong
    2022, 42 (8):  1103-1109. 
    doi: 10.3969/j.issn.1674-8115.2022.08.015

    Abstract ( 53 )   HTML ( 8 )   PDF (1995KB) ( 9 )  

    Objective ·To investigate the association of exposure to parabens, a class of common used preservatives in food, drugs and personal care products, with pulmonary function in preschool children. Methods ·A total of 136 preschool children aged 5?7 years old were recruited from Shanghai children's Hospital,Shanghai Jiao Tong University School of Medicine from August 2019 to January 2020. Baseline information such as children's age, height, body mass index (BMI), and annual family income were collected. Urine samples were taken, and the concentrations of five kinds of urinary paraben were detected by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS), including methyl 4-hydroxybenzoate (MeP), ethyl 4-hydroxybenzoate (EtP), propyl 4-hydroxybenzoate (PrP), butyl 4-hydroxybenzoate (BuP) and benzyl 4-hydroxybenzoate (BzP). The forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, peak expiratory flow (PEF), forced expiratory flow between the 25th and 75th percentile of forced vital capacity (FEF25-75) were measured by using pulmonary function instrument. Multiple linear regressions were conducted to examine the associations between paraben exposure and pulmonary function indexes in children. Results ·In the 136 preschool children, the average age and BMI were (5.76±0.84) years and (15.78±2.96) kg/m2 respectively, 59 (43.4%) were males, and 13 (9.6%) were obese children. The detection rates of MeP, EtP, PrP, BuP and BzP were 97.8%, 86.8%, 99.3%, 77.9% and 11.8%, respectively; the median creatinine-adjusted levels of MeP, EtP, PrP, and BuP were 36.12, 3.88, 1.50 and 0.06 μg/g, respectively. After adjusting age, sex, height, BMI, preterm birth, and annual family income, the results of multiple linear regressions suggested significantly negative associations between MeP and FVC (β=-0.018, 95%CI-0.035?-0.001, P=0.044), PrP and FEV1 (β=-0.032, 95%CI-0.051?-0.013, P=0.013), BuP and FVC (β=-0.018, 95%CI-0.034?-0.002, P=0.038), as well as BuP and FEV1 (β=-0.021, 95%CI-0.041?-0.001, P=0.047). Conclusion ·Preschool children in Shanghai may be widely exposed to parabens, and exposure to parabens is negatively associated with child pulmonary function.

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    Path analysis of influencing factors of outpatient cardiac rehabilitation program participation of patients with coronary heart disease in Shanghai
    LIU Xia, WEN Fule, ZHANG Yaqing
    2022, 42 (8):  1110-1115. 
    doi: 10.3969/j.issn.1674-8115.2022.08.016

    Abstract ( 56 )   HTML ( 7 )   PDF (1430KB) ( 11 )  

    Objective ·To understand the current situation of outpatient cardiac rehabilitation participation of patients with coronary heart disease (CHD) in Shanghai and explore its influencing factors. Methods ·From October to December 2017, by using the convenience sampling method, a cross-sectional study was conducted to obtain information of CHD patients who visited the cardiovascular outpatient departments from 7 tertiary hospitals in Shanghai, concerning sociodemographics, Chinese/Mandarin Cardiac Rehabilitation Barriers Scale (CRBS-C/M) and Cardiac Rehabilitation Information Awareness Questionnaire (CRIAQ). The viarate analysis and Spearman analysis were applied to correlation analysis and the structural equation model was applied to path analysis. Results ·A total of 273 questionnaires were distributed and 234 valid questionnaires were collected with the effective rate of recovery at 85.7%. The average age of the respondents was (66.78±10.42) years. Only 17 (7.26%) patients self-reported that they participated in the outpatient cardiac rehabilitation at least once after discharge. There was no significant difference in participation rates in different sociodemographics. The Spearman correlation analysis demonstrated that cardiac rehabilitation information awareness, perceived cardiac rehabilitation barriers, and participation in outpatient cardiac rehabilitation were significantly correlated (all P=0.000). Path analysis showed that the cardiac rehabilitation information had a direct promoting effect on the behavior of participating in outpatient cardiac rehabilitation (β=0.384, P=0.000), and could also be partially mediated by cardiac rehabilitation barriers. Conclusion ·Regarding the patients with CHD, the awareness of cardiac rehabilitation information can directly promote their participation in outpatient cardiac rehabilitation, and can also partially alleviate the adverse effect of perceived cardiac rehabilitation barriers. Health care providers should start with improving patients' cardiac rehabilitation information and adopt various forms of health education to improve their cardiac rehabilitation cognition and overcome perceived cardiac rehabilitation barriers. Ultimately, the participation in outpatient cardiac rehabilitation programs will be facilitated for patients with CHD.

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    Review
    Research progress in the mechanism and intervention of tendon adhesion
    SHA Pan, ZHAO Xuewen, ZHU Haotian, GAO Chongzhou, LIU Shen
    2022, 42 (8):  1116-1121. 
    doi: 10.3969/j.issn.1674-8115.2022.08.017

    Abstract ( 88 )   HTML ( 13 )   PDF (1324KB) ( 56 )  

    As one of the clinical challenges, tendon adhesion is a common complication after the repair of tendon injuries and difficult to treat. In recent years, with the continuous updating and development of medical science, research into the mechanism of tendon healing has been advanced, which provides a theoretical basis for the prevention and treatment of tendon adhesion and functional recovery after surgery. The key to prevent tendon adhesion is to inhibit exogenous healing and inflammatory reaction and to promote endogenous healing. The occurrence of tendon adhesion is mainly related to transforming growth factor-β (TGF-β), basic fibroblast growth factor, vascular endothelial growth factor and other cytokines. Additionally, TGF-β/Smad signal transduction pathway is of significance. Clinically, improvement of suturing methods and early rehabilitation activities play an important role in the prevention and treatment of tendon adhesion, the principle of which is related to the effect of mechanical loading on cell behavior. The combination of materials and drugs is the current research hotspot in the prevention and treatment of tendon adhesion. The existing anti-adhesion membrane mainly acts as physical barrier, and the drug-loaded membrane can efficiently inhibit adhesion by inhibiting inflammatory responses, regulating cell proliferation and metabolism, reducing oxidative stress, and inhibiting TGF-β. This article presents a review of recent research progress in the mechanisms of tendon adhesion and interventions in the areas of surgery, rehabilitation, materials and drugs, in order to promote the transformation and application of basic research, which may provide reference significance for clinical prevention and treatment of tendon adhesion.

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    Progress in metabolism of the immune cells in tumor microenvironment
    LIN Jiayu, QIN Jiejie, JIANG Lingxi
    2022, 42 (8):  1122-1130. 
    doi: 10.3969/j.issn.1674-8115.2022.08.018

    Abstract ( 89 )   HTML ( 17 )   PDF (2370KB) ( 92 )  

    Metabolic reprogramming refers to cells' mechanism to change their metabolic patterns in order to meet the increased energy demand caused by growth and proliferation. By way of metabolic reprogramming such as the Warburg effect, tumor cells gain rich energy to support their own survival, growth, and metastasis. The tumor microenvironment (TME) is the internal environment in which tumor cells survive, containing not only tumor cells, but also stromal cells, immune cells, and other components that are closely related to tumor cells. Meanwhile, tumor cells regulate intercellular function and signaling via secreting cytokines, metabolites, and other molecules and shape a commonly hypoxic, acidic, and nutrient-deprived TME which contributes the most to immune resistance. However, rapidly proliferating tumor cells compete for relatively scarce nutrients with immune cells, consequently, producing an immunosuppressive metabolism microenvironment. Under the influence of immunosuppressive TME, immune cells generate tolerance phenotype-related metabolic adaptations through metabolic reprogramming to satisfy their own needs and further perform anti-tumor or immunosuppressive roles. The response of immune cells to tumor cells mainly depends on respective unique metabolic pathways, which are related to the type and function of immune cells. Moreover, the functional properties of immune cells are directly associated with the immunotherapy effects. Regulating metabolic pathways of immune cells provides a great direction for cancer therapy. In this paper, the main metabolic pathways of immune cells in TME is described, the relationship between their metabolic characteristics and immune functions is summarized, and the mechanism of metabolic pathways underlying the functions of immune cells is further discussed, providing new insights for unveiling tumor immunosuppressive microenvironment and improving the efficacy of tumor immunotherapy.

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    Advances in application of adipose-derived mesenchymal stem cells in autoimmune diseases
    LI Yuehua, LI Qingfeng, XIE Yun
    2022, 42 (8):  1131-1138. 
    doi: 10.3969/j.issn.1674-8115.2022.08.019

    Abstract ( 55 )   HTML ( 9 )   PDF (1319KB) ( 8 )  

    The occurrence and development of autoimmune diseases is due to the decrease or even destruction of the patient's autoimmune tolerance, and excessive production of autoantibodies and/or sensitized lymphocytes in the body, resulting in histopathological changes and clinical phenotypes. At present, the main clinical treatment is the drug-based non-specific immunosuppression therapy. Although it can relieve some patients' symptoms, for severe patients, the effect is often not ideal. In recent years, with the in-depth study of mesenchymal stem cells (MSCs), people's understanding of their characteristics has gradually expanded from highly self-renewal and differentiation ability to immunomodulatory function. At the same time, the research direction based on MSCs has gradually shifted from regenerative medicine to the field of autoimmunology. With the development of preclinical and clinical trials, systemic or local application of adipose-derived mesenchymal stem cells (AD-MSCs) has been gradually recognized as one of the effective methods for clinical treatment of autoimmune diseases. In this review, the biological characteristics of AD-MSCs and their application to autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, inflammatory bowel disease, systemic scleroderma, and psoriasis, are highlighted.

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    Progress in the study of the effect of bilirubin on the central nervous system and its mechanism
    LIU Zhenqi, SHI Haibo, YIN Shankai
    2022, 42 (8):  1139-1144. 
    doi: 10.3969/j.issn.1674-8115.2022.08.020

    Abstract ( 62 )   HTML ( 8 )   PDF (1209KB) ( 43 )  

    In the World Hearing Report published by the World Health Organization in 2021, neonatal jaundice hyperbilirubinemia is identified as one of the major risk factors for sensorineural deafness, which can lead to multisystem neurological damage, including the auditory center. Bilirubin is a physiological metabolite of heme, and the basic physiological metabolic transport pathways of bilirubin have been fully understood. But the incidence of neonatal hyperbilirubinemia is still at a high level. Severe hyperbilirubinemia seriously affects neonatal neurological development, and even has a risk of disability. In the past 20 years, this electrophysiology research team of the Department of Otolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine (Sixth Hospital for short) has been the first in the world to conduct studies on the excitability of bilirubin on neurons, reveal the effects of bilirubin on a series of ion channels and receptors, elaborate the excitotoxic mechanism of bilirubin-induced central damage, and explore potential antagonistic drugs. This paper combined previous studies with the findings of the electrophysiology research team of the Sixth Hospital to describe the effects of bilirubin on the central nervous system and its mechanisms, and discuss the interaction between bilirubin and glial cells and the potential benefits of bilirubin. The mechanisms of bilirubin's toxicological effects are complex and include a wide range of regulatory effects of high bilirubin concentrations on synaptic structures, ion channels and receptors, lipid bilayer membranes and energy metabolism. This review aims to provide theoretical support for better understanding and prevention of bilirubin neurotoxicity.

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    Research progress on the role of regulatory T cells in ocular surface diseases
    A Tingxi, SHAO Chunyi, FU Yao
    2022, 42 (8):  1145-1150. 
    doi: 10.3969/j.issn.1674-8115.2022.08.021

    Abstract ( 77 )   HTML ( 8 )   PDF (1234KB) ( 13 )  

    As the external barrier of the eyeball, the ocular surface tissue, composed of the cornea, the conjunctiva, the eyelids, the meibomian glands, and the lacrimal gland, is exposed to the environment. In addition to keeping the cornea smooth and wet, the ocular surface is equipped with immune cells and related factors, which are capable of fighting against pathogens through innate and adaptive immune responses and preventing unnecessary or excessive inflammatory reactions against autoantigens or harmless foreign antigens through several regulatory mechanisms. The disorder of immune regulation is at the core of many ocular surface diseases. As an important part of the ocular surface microenvironment, regulatory T cells (Treg cells) actively participate in the suppression of abnormal or excessive immune responses towards the auto, microbial and environmental antigens through various mechanisms, and play a key role in inducing immune tolerance and regulating immune balance. Functional and numerical defects of Treg cells can trigger disruption of the immune homeostasis, leading to or promoting the occurrence of ocular surface diseases. In recent years, more and more researchers are focusing on the role and related molecular mechanisms of Treg cells in the occurrence and development of ocular surface diseases. Some preclinical studies have shown that Treg cell-related immunotherapy has great therapeutic potential in ocular surface diseases. Therefore, this article reviews the biological functions of Treg cells and their roles in the ocular surface diseases, such as dry eye disease, allergic diseases, infectious diseases, corneal transplantation rejection, and tissue repair, and then discusses the promising application prospects of Treg cells therapy in the field.

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    Brief original article
    Clinicopathological characteristics of CIC-rearranged sarcoma in children
    XING Zhengwen, WU Ying, WANG Xueli, WANG Qingyu, WANG Wenting, LI Zhi, ZHANG Bin, JIN Jing
    2022, 42 (8):  1151-1157. 
    doi: 10.3969/j.issn.1674-8115.2022.08.022

    Abstract ( 79 )   HTML ( 7 )   PDF (5387KB) ( 7 )  

    Objective ·To analyze the clinical, pathological and molecular genetic characteristics of CIC-rearranged sarcoma (CRS) in children to improve the understanding of small round cell sarcoma newly proposed in the 5th edition of the WHO Classification of Soft Tissue and Bone Tumours. Methods ·Data of 54 patients with small round cell undifferentiated sarcoma diagnosed in Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine from January 2019 to April 2021 were collected. Five cases of pediatric CRS with complete clinical, imaging, pathological and follow-up data were selected to analyze their clinicopathological features. Results ·There were 3 males and 2 females in the 5 CRS patients aged from 5 months to 10 years. There were 3 asymptomatic children, and chest and back pain and projectile vomiting were the first symptoms in 2 cases respectively. All CT images showed cystic, solid or mixed irregular soft tissue masses of varying sizes. Histopathological examination showed that the average maximum diameter of the tumor was 12.5 cm, and the cut surface was grayish white or grayish brown, with the appearance of rotten fish flesh. The histopathology was mainly distributed in small round diffuse sheets. Immunohistochemistry showed CD99 diffuse membrane positive or focal positive, WT1 diffuse nuclear positive, and BCL2, CD56, FLI1 and ERG expressed to varying degrees. Fluorescence in situ hybridization (FISH) test showed that EWSR1 (22q12) was negative and CIC (19q13) gene was rearranged. Meanwhile, some children also had CIC fusion gene mutations, including 2 CIC-DUX4 fusion cases and 1 CIC-NUTM1 fusion case. All patients were treated with surgery and postoperative adjuvant chemotherapy. Follow?up data were available in all the five cases (mean 21.4 months); one patient died of disease, whereas two patients were alive with unresectable recurrent tumour, and the remaining two patients were alive with no evidence of disease. Conclusion ·Pediatric CRS is a rare malignant soft tissue tumor with asymptomatic or non-specific symptoms, easy metastasis and poor prognosis. Immunohistochemistry combined with EWSR1 and CIC rearrangement-related molecular examination is helpful for the diagnosis of Ewing's sarcomatoid soft tissue tumors, and further detection of CIC fusion gene may be helpful for prognosis estimation.

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    Case report
    Two cases of hemiplegic migraine caused by ATP1A2 gene mutation
    DING Siqi, HUANG Xiaojun, ZHAN Feixia, TIAN Wotu, CAO Li
    2022, 42 (8):  1158-1162. 
    doi: 10.3969/j.issn.1674-8115.2022.08.023

    Abstract ( 62 )   HTML ( 10 )   PDF (1613KB) ( 36 )  

    Both 2 cases developed hemiplegic migraine at an early age. The clinical manifestations were almost the same, featuring visual disturbance (such as visual flash) and hemiplegia or hemiparesis. A unilateral pulsating headache with nausea and vomiting developed soon after these auras which lasted about half an hour. The headache was relieved after rest. No abnormality was found in the neurological examination, cranial CT, MRI, electroencephalogram and metabolic disease examination. According to The International Classification of Headache Disorders, 3rd edition (ICHD-3) , both 2 cases were presented as typical pure hemiplegic migraine without other neurological disorders. Genetic sequencing showed ATP1A2 gene mutation in the 2 patients. Heterozygous mutation c.G2284A/p.G762S was present in case 1 and it has previously been shown to be a pathogenic mutation. Case 2 was identified with c.C3022T/p.R1008W, and no related reports were found in the previous literature and databases. According to the standard of American College of Medical Genetics and Genomics (ACMG), c.G2284A/p.G762S in case 1 was as "likely pathogenic" and c.C3022T/p.R1008W in case 2 was as "uncertain significance".

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