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    Establishment and optimization of co-culture technology for breast cancer organoids
    Tian-hao ZHOU, Zhao-chen XIN, Shao-qian DU, Yuan CAO, Jing-xuan XU, Zeng-hong LAO, Hong-xia WANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 1017-1024.   DOI: 10.3969/j.issn.1674-8115.2021.08.004
    Abstract345)   HTML199)    PDF(pc) (4693KB)(223)       Save
    Objective

    ·To improve the cultivating and passaging method of breast cancer organoids, and establish a co-culture system enriching cancer associated fibroblasts (CAFs).

    Methods

    ·Different types of collagenases (type Ⅰ, type Ⅲ and type Ⅳ) were used to digest fresh tissues from 5 breast cancer patients. The number of cells after tissue digestion was counted by cell counting method, and cell viability was analyzed by cell flow cytometry. Three-dimensional culture of primary breast cancer single cells was carried out by using culture system containing different contents of fibroblast growth factor 7 (FGF7), FGF10 and epidermal growth factor (EGF). The success rate of cell culture and the growing status of organoids were observed and compared. Different centrifugation speeds were used to compare the advantages and disadvantages of passaging methods and simplify the passaging steps. CCK8 assay was used to study the effect of CAFs on the growth of organoids in the co-culture system of primary CAFs and organoids, and the morphological changes of organoids were observed under optical microscope.

    Results

    ·Compared with type Ⅰ and type Ⅲ collagenase, type Ⅳ collagenase got the highest cell yields (P=0.045, P=0.017), and maintained the highest cell viability (P=0.005, P=0.048). By optimizing the composition of organoid medium (omitting FGF7 and FGF10, reducing EGF concentration) and passaging process (improving centrifugal velocity to 900×g), a more economical, effective and rapid method of organoid culture was obtained. Compared with organoids cultured alone, the growth rate (P<0.05) and heterogeneity of organoids increased when organoids were co-cultured with CAFs.

    Conclusion

    ·The optimized culture system can significantly increase the success rate of organoids, simplify the culture steps and reduce the culture cost. The establishment of primary CAFs and organoids co-culture system provides a good in vitro model for the study of breast cancer heterogeneity and tumor microenvironment.

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    Research progress and development trend of lower extremity exoskeleton rehabilitation robot
    Jiyu HAN, Yanhong WANG, Daqian WAN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2022, 42 (2): 241-246.   DOI: 10.3969/j.issn.1674-8115.2022.02.017
    Abstract328)   HTML410)    PDF(pc) (917KB)(150)       Save

    Lower limb motor dysfunction caused by various causes is an important public health problem in the world today. Lower extremity exoskeleton rehabilitation robot is a new type of wearable bionic device, which is mainly used to realize the standing and walking of patients with lower extremity motor dysfunction. It is a hot research topic in rehabilitation medicine at present. By reviewing the history of lower extremity exoskeleton rehabilitation robot, some breakthroughs and developments are found to have been made in this field in recent years. In the future, if we can overcome the technical problems such as portability, intelligence and modularization, it will be possible to maximize the recovery of patients with lower limb dysfunction. In this paper, the key technologies and clinical applications of wearable lower extremity exoskeleton rehabilitation robot are reviewed comprehensively, and new prospects for the research and development in this field are proposed.

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    Review of immunosuppressive tumor microenvironment of pancreatic cancer
    Jing-wei LI, Li-wen WANG, Ling-xi JIANG, Qian ZHAN, Hao CHEN, Bai-yong SHEN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 1103-1108.   DOI: 10.3969/j.issn.1674-8115.2021.08.018
    Abstract321)   HTML69)    PDF(pc) (908KB)(192)       Save

    Pancreatic cancer is a highly malignant tumor. The difficulty of early diagnosis and scarcity of effective clinical treatment strategies lead to poor prognosis. Tumor microenvironment (TME) of pancreatic cancer is composed of tumor cells, immune cells, stromal cells, extracellular matrix and soluble factors. TME plays an important role in the development, progression, invasion and metastasis of tumors. The pancreatic cancer microenvironment has significant immune cell infiltration, which is highly immunosuppressive. On the one hand, tumor cells edit the immune system so that cancer cells cannot be recognized by the immune system; on the other hand, they can recruit and activate various immunosuppressive cells such as pancreatic stellate cells, myeloid-derived inhibitory cells, tumor-associated macrophages, regulatory T cells and so on. These immunosuppressive cells can secrete immunosuppressive molecules, affect the function of anti-tumor immune cells, inhibit the host′s anti-tumor immune response, lead to tumor immune escape, and promote tumor development and metastasis. In this review, the mechanisms and effects of these immunosuppressive components are discussed and the updated results of immunotherapy on pancreatic cancer are studied, which may provide novel insights on TME and immunotherapy of pancreatic cancer.

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    Haptoglobin suppresses hepatocyte ferroptosis via inhibition of the ERK1/2 signaling pathway
    Qian WEI, Ying-ting ZHANG, Long-shuai LIN, En-jun HE, Yong-yuan HE, Ying-hong SU, Cheng-cheng DUAN, Si-yuan WANG, Qing-hua ZHAO, Qian ZHAO, Ming HE
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 999-1008.   DOI: 10.3969/j.issn.1674-8115.2021.08.002
    Abstract223)   HTML81)    PDF(pc) (4390KB)(172)       Save
    Objective

    ·To explore the role and mechanism of haptoglobin (Hp) in hepatocyte ferroptosis.

    Methods

    ·Thirteen 8-week-old C57BL/6J male mice were randomly divided into two groups: one group of mice were fed with normal iron diet (NID group, n=5) and the other were fed with high iron diet (HID group, n=8). After 12 weeks, the murine serums and livers were collected from both groups. Liver injury, histopathological changes, hepatic fibrosis, iron deposition and peroxidation in murine liver tissues were determined by serum index test, hematoxylin-eosin (H-E) staining, Sirius red staining, Prussian blue staining and 4-hydroxynonenal (4-HNE) staining, respectively. RNA-sequencing (RNA-seq) and bioinformatics were used to analyze the effect of high iron diet on the expression of transcriptome in the murine livers and to screen new candidate genes that might regulate ferroptosis. After Hp was overexpressed or knocked down in mouse liver cells (AML-12), RAS-selective lethal small molecule 3 (RSL3) or/and extracellular regulated protein kinases 1/2 (ERK1/2) inhibitor SCH772984 was/were added to cells. The role and mechanism of Hp in hepatocyte ferroptosis were determined by cell counting, real-time PCR, C11-BODIPY581/591 immunofluorescence and flow cytometry.

    Results

    ·After 12 weeks of feeding, the levels of glutamic-pyruvic transaminase (GPT) and glutamic-oxalacetic transaminase (GOT) in the HID group significantly increased compared with the NID group. The high iron diet induced hepatocytes death, hepatic fibrosis, iron deposition and lipid peroxidation products accumulation. RNA-seq analysis and bioinformatics results showed that acute phase response, catalytic activity response, antioxidant activity and hemoglobin binding signaling pathways were significantly regulated in the livers of HID mice, and Hp mRNA decreased significantly. Furthermore, the mRNA and protein expression levels of Hp in liver tissues of HID mice and in AML-12 hepatocytes treated with RSL3 obviously decreased. Importantly, Hp significantly alleviated lipid peroxidation and ferroptosis induced by RSL3 in AML-12 hepatocytes. Meanwhile, Hp suppressed RSL3-induced phosphorylation of ERK1/2 in AML-12 hepatocytes. Moreover, ERK1/2 inhibitor SCH772984 totally reversed the aggravation of hepatocyte ferroptosis induced by Hp knockdown.

    Conclusion

    ·Hp is a novel inhibitory molecule in hepatocytes ferroptosis, which alleviates hepatocyte ferroptosis and liver injury by inhibiting ERK1/2 signaling pathway.

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    Report of 3 cases of 47,XXX syndrome with growth retardation
    YANG-Li, Ya-qin FENG, Yu YANG, Li-ling XIE, Di-lan WANG, Hui HUANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (11): 1425-1428.   DOI: 10.3969/j.issn.1674-8115.2021.11.004
    Abstract204)   HTML111)    PDF(pc) (1104KB)(135)       Save

    To analyze the clinical data of 3 children with growth retardation, including height, chromosome karyotype, and the levels of growth hormone, insulin-like growth factor-1 and gonadal development. All the 3 cases of children were found to be slow in growth rate, no special face, and normal level of insulin-like growth factor-1; the 3 cases all underwent growth hormone provocation test, of which 1 case was partial growth hormone deficiency and 2 cases were idiopathic short; 3 cases of chromosomal karyotypes were 47, XXX, in line with the diagnosis of super-female syndrome.

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    Review of clinical application of peripheral neuropathy scales
    Qun-feng WANG, Li CAO, Xing-hua LUAN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (11): 1518-1523.   DOI: 10.3969/j.issn.1674-8115.2021.11.018
    Abstract204)   HTML77)    PDF(pc) (867KB)(109)       Save

    Peripheral neuropathy (PN) refers to a group of diseases caused by the dysfunction and structural changes of peripheral motor, sensory and autonomic nerves. Scales for screening and assessing PN are continuously being used in clinical practice. This article summarizes PN score scales for four kinds of PN, including chronic inflammatory demyelinating polyradiculoneuropathy, Charcot-Marie-Tooth disease, diabetic PN and neuropathic pain, aiming to improve medical staff's understanding and application ability of the PN assessment scale.

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    Construction of a metastasis prediction model of microsatellite instability-high colorectal cancer based on differentially expressed gene assembly
    Ying XU, Yi-min CHU, Da-ming YANG, Ji LI, Hai-qin ZHANG, Hai-xia PENG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (9): 1197-1206.   DOI: 10.3969/j.issn.1674-8115.2021.09.010
    Abstract193)      PDF(pc) (5369KB)(116)       Save
    Objective

    ·To explore the potential key genes and the gene expression characteristics of microsatellite instability-high (MSI-H) colorectal cancer (CRC) with metastasis at the transcriptome level, and establish a metastasis prediction gene model.

    Methods

    ·The transcriptome data of MSI-H CRC patients was obtained from The Cancer Genome Atlas database. The patients were divided into metastatic group (21 patients) and non-metastatic group (42 patients). The differentially expressed genes (DEGs) between the two groups were analyzed by Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) to annotate, and cluster DEGs and enrich the signaling pathways. STRING and Cytoscape were used to select the hub genes. Nomogram was drawn based on the selected DEGs. The cross validation of the model was performed by Bootstrap method. Survival analysis was done to explore the influences of each gene in the nomogram on progression-free survival (PFS) of MSI-H CRC.

    Results

    ·A total of 245 DEGs were obtained from the metastatic group and non-metastatic group, among which 204 genes were up-regulated and 41 genes were down-regulated. GO analysis showed that DEGs were mainly clustered in ion transmembrane transport, chloride transmembrane transport and chloride channel activity in terms of biological process and molecular function. In terms of cellular component, DEGs were mainly clustered in extracellular region and extracellular space. GSEA showed that the neuroactive ligand-receptor interaction and metabolic pathways were enriched in the up-regulated genes. The top 10 hub genes in the protein-protein interaction network of the up-regulated genes were screened by Cytoscape. The metastasis prediction gene model, which was set up based on the top 10 DEGs with the lowest adjusted P value and high physiological relevance to tumor, had certain predictive efficiency [area under curve (AUC)=0.975 for training, AUC=0.920 for validation]. The expression levels of AC078993.1 and IGLJ2 (immunoglobulin lambda joining 2) were significantly negatively correlated with PFS of MSI-H CRC (P=0.011, P=0.005).

    Conclusion

    ·The changes in ion channels and extracellular environment may have important impacts on metastasis of MSI-H CRC. Neuroactive ligand-receptor interaction and metabolic pathways may be two important signaling pathways for metastasis of MSI-H CRC. A metastasis prediction gene model is established, which can provide reference for the follow-up related clinical researches.

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    Application of OCT and OCTA to chronic ocular ischemic diseases caused by carotid stenosis
    Gong CHEN, Xi SHEN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 1109-1113.   DOI: 10.3969/j.issn.1674-8115.2021.08.019
    Abstract185)   HTML102)    PDF(pc) (932KB)(54)       Save

    Carotid stenosis is one of the major causes of chronic ocular ischemic diseases, which are often manifested as venous stasis retinopathy and ocular ischemic syndrome, and the latter can lead to neovascular glaucoma. At present, fundus fluorescein angiography, indocyanine green angiography, color Doppler flow imaging and carotid artery imaging help to establish the diagnosis. Recently, optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) have been gradually applied to make diagnosis and follow-up in chronic ocular ischemic diseases caused by carotid stenosis as novel, non-invasive, rapid and high-resolution techniques. This review summarizes recent applications of OCT and OCTA to chronic ocular ischemic diseases caused by carotid stenosis.

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    Effects of knockdown of immunoregulatory protein B7 - H3 gene on malignant proliferation, invasion and stem cell-like characteristics of bladder cancer cells
    Xiao-han WANG, Yun-lin YE, Kang-hua XIAO, Zhi-xin ZHAO, Jing-ya WU
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (11): 1454-1460.   DOI: 10.3969/j.issn.1674-8115.2021.11.008
    Abstract185)   HTML110)    PDF(pc) (2429KB)(65)       Save
    Objective

    ·To investigate the effect of gene interfering with immune regulatory protein B7-H3 on malignant proliferation and stemness characteristics of bladder cancer J82 cells.

    Methods

    ·Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect shRNA interference efficiency. The proliferation of J82 cells was detected by clone formation assay. Cell apoptosis was detected by flow cytometry. Cell invasion was detected using Transwell asssay. The tumor-cloning ability was observed using tumor sphere formation experiment. Apoptosis, invasion, and expression and stemness-related proteins were detected by Western blotting.

    Results

    ·B7-H3 is highly expressed in bladder cancer tissues and bladder cancer cell lines (P=0.000). shRNA2 was identified as the most efficient interference with B7-H3 gene in three shRNAs (P=0.000). The interference of B7-H3 inhibited the proliferation, invasion, tumor cloning ability and stem cell-like characteristics of J82 cells (P=0.000). Furthermore, B7-H3 interference promoted the apoptosis of J82 cells (P=0.000).

    Conclusion

    ·The gene interference of immunoregulatory protein B7-H3 can inhibit the malignant proliferation, invasion and stemness characteristics of bladder cancer J82 cells, providing a new possibility and effective evidence for the treatment of bladder cancer.

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    Progress in research on the mechanism of drug resistance to conventional chemotherapeutic drugs in children with acute lymphoblastic leukemia
    Yanyan LIN, Yan XU, Hui LI
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2022, 42 (2): 211-217.   DOI: 10.3969/j.issn.1674-8115.2022.02.012
    Abstract184)   HTML221)    PDF(pc) (850KB)(103)       Save

    Acute lymphoblastic leukemia (ALL) has the highest incidence of hematological tumors in children, accounting for about one-third of all childhood cancer cases. With the continuous optimization of the treatment plan and the expansion of health care coverage in China, remarkable improvements have been achieved in the treatment of childhood ALL, and the overall survival rate of more than 5 years has reached 90%. Lack of effective treatment and unacceptably high recurrence rate are the leading causes of severe decrease in the survival and quality of life of children with drug resistance. In recent years, pathogenesis and regulation mechanism of ALL drug resistance has become a hot topic and a difficulty of research at home and abroad. Studies have shown that children with ALL may not only antagonize a certain chemotherapy (chemotherapeutic) drug, but also have a thorny situation of multi-drug resistance. Therefore, it is of great significance to improve the research on the mechanism of drug resistance of ALL to improve the prognosis of children with ALL. This review summarizes recent research progress in drug resistance mechanisms of conventional chemotherapy drugs for childhood ALL, including hormones, antimetabolite drugs (folate antagonists, thiopurines, and amino acid metabolizing drugs), alkaloids and anthracyclines, in order to provide theoretical basis for coping with clinical drug resistance.

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    Expression of protein arginine methyltransferase 5 in lung cancer and its mechanism of promoting lung cancer
    Bing-qian ZHOU, Li HAN, Zhe-yi CHEN, Shi-yu CHEN, Ying-xia ZHENG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 1009-1016.   DOI: 10.3969/j.issn.1674-8115.2021.08.003
    Abstract183)   HTML84)    PDF(pc) (3871KB)(68)       Save
    Objective

    ·To investigate the expression of protein arginine methyltransferase 5 (PRMT5) in lung cancer and its effect on proliferation, migration and invasion of lung cancer cells.

    Methods

    · Immunohistochemistry was used to detect the expression of PRMT5 in 73 pairs of lung cancer tissues and adjacent tissues, and its correlation with clinical characteristics of patients was analyzed. After PRMT5 was down-regulated in lung cancer cell line NCI-H1299, the effects of PRMT5 on cell proliferation, migration and invasion were observed by CCK8 assay and Transwell chamber, and the expressions of E-cadherin, vimentin and transcription factor SNAI1 were detected by Western blotting. The expression of PRMT5 in tumor cell lines and lung cancer tissues was analyzed by using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database, respectively, and the relationship between the expression of PRMT5 in tissues and the prognosis of lung cancer patients was further analyzed.

    Results

    ·Immunohistochemistry showed that the expression of PRMT5 in lung cancer tissues was significantly higher than that in adjacent tissues (P=0.000), and the expression of PRMT5 in stage Ⅲ?Ⅳ was higher than that in stage Ⅰ?Ⅱ (P=0.033). After PRMT5 down-regulation, the proliferation, migration and invasion ability of NCI-H1299 cells decreased, the expression of E-cadherin increased and the expression of vimentin and SNAI1 decreased. The lung cancer sequencing data of TCGA database showed that the expression of PRMT5 in lung cancer tissues was significantly higher than that in normal lung tissues, and the lung adenocarcinoma patients and the lung squamous cell carcinoma patients with higher expression of PRMT5 had lower overall survival rate (P=0.005) and relapse-free survival rate (P=0.028), respectively.

    Conclusion

    · PRMT5 is highly expressed in lung cancer tissues, which can promote the proliferation, migration and invasion of lung cancer cells. High expression of PRMT5 is associated with poor prognosis of lung cancer.

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    Analysis of prognostic factors of radiotherapy in children with Ⅲ-Ⅳ neuroblastoma
    Jun-jun ZHOU, Jie ZHAO, Jing-yan TANG, Ma-wei JIANG, Xiu-mei MA, Yong-rui BAI
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 1051-1055.   DOI: 10.3969/j.issn.1674-8115.2021.08.009
    Abstract182)   HTML88)    PDF(pc) (991KB)(96)       Save
    Objective

    ·To analyze the factors affecting the survival and prognosis of the children with medium-, high-, and very high-risk neuroblastoma (NB) in stage Ⅲ?Ⅳ after radiation therapy.

    Methods

    ·A total of 132 cases of neuroblastoma patients from 2008 to 2018 who received local radiotherapy in the Department of Hematology and Oncology, Shanghai International Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, and the Department of Radiation Oncology, Renji Hospital and Xinhua Hospital were included. Treatment options included chemotherapy, surgery, autologous bone marrow transplantation (ABMT), radiotherapy, and later 13-cis-RA maintenance therapy. SPSS 19.0 software was used for the calculation of event-free survival (EFS) and overall survival (OS) rates, as well as univariate and multivariate survival analysis.

    Results

    ·By the end of the follow-up, the EFS rates for the all patients were 87.41% in 1 year, 55.25% in 2 years, 45.02% in 3 years, and 38.67% in 5 years, and the OS rates were 96.02% in 1 year, 83.54% in 2 years, 72.15% in 3 years, and 57.79% in 5 years, respectively. The medium follow-up time was 40.3 months. Univariate survival analysis suggested that the staging, risk grouping, brain metastasis or not, blood lactic acid dehydrogenase and serum ferritin levels were associated with EFS and OS (P<0.05). The presence or absence of bone marrow infiltration was a related factor of EFS (P=0.007), but not OS-related. Factors such as the child′s gender, whether the child was treated with ABMT, the amplification of MYCN proto-oncogene, and the presence of liver metastasis had no significant correlation with EFS or OS. Multivariate survival concluded that brain metastasis was an independent prognosis factor for EFS and OS.

    Conclusion

    ·The amplification of MYCN gene and ABMT treatment may not significantly affect the radiotherapy efficacy and overall survival of stage Ⅲ?Ⅳ NB children. However, the presence of brain metastasis is an independent prognostic factor related to survival and disease progression after radiotherapy.

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    Construction and application value of prognosis-associated miRNA prediction model in gastric cancer patients
    Ben YUE, Gao-ming WANG, Lu-di YANG, Ran CUI, Feng-rong YU
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (11): 1436-1445.   DOI: 10.3969/j.issn.1674-8115.2021.11.006
    Abstract182)   HTML124)    PDF(pc) (4151KB)(60)       Save
    Objective

    ·To construct a prognosis-associated microRNA (miRNA) prediction model in gastric cancer patients based on bioinformatics analysis and evaluate its application value.

    Methods

    ·The clinicopathological data of gastric cancer patients were downloaded from the Cancer Genome Atlas (TCGA). There were 258 males and 139 females with a median age of 67 years. Three hundred and fifty-six of the 397 patients had complete clinicopathological data. The 397 patients were allocated into training cohort consisting of 278 patients and validation cohort consisting of 119 patients using the random sampling method, with a ratio of 7∶3. A miRNA sequencing dataset GSE93415 containing 20 pairs of gastric cancer and corresponding adjacent normal tissue was downloaded from Gene Expression Omnibus database. The candidate miRNAs were selected from differentially expressed miRNAs in gastric cancer and adjacent tissue. A prognosis associated miRNA prediction model was constructed upon survival-associated miRNAs which were selected from candidate miRNAs through LASSO-Cox regression analysis. The performance of prognosis-associated miRNA prediction model was validated in the training cohort and validation cohort. The reliability of the model was evaluated by using Log-Rank test, and the accuracy of the model was evaluated by using the area under curve (AUC) of the receiver operating characteristic curves. Gene expression profiles and algorithms in the pRRophetic package were utilized to predict patients' sensitivity to chemotherapy drugs. Calibration curves were used to verify the accuracy of the nomogram. Consistency index (C-index) was used to check the consistency of the nomogram and other factors. Decision curve analysis (DCA) was employed to predict the contribution of candidate factors to clinical decision making.

    Results

    ·① There was no significant difference in the baseline and overall survival between the training cohort and validation cohort (P>0.05). ② There were 111 differentially expressed miRNAs calculated from GSE93415 dataset, of which 20 were up-regulated in tumor tissue while 91 were down-regulated. Fifty-nine miRNAs were selected as candidate miRNAs after filtration. ③ Among the 59 candidate miRNAs, 5 survival-associated miRNAs were selected, including let-7i-5p, let-7f-5p, miR-708-5p, miR-135b-5p and miR-100-5p. The differential expression patterns of gastric cancer to adjacent tissue were all down-regulation, with the fold change of 2.55, 2.78, 2.17, 3.08 and 3.26. Risk score = (-0.049×let-7i-5p expression level -0.033 2×let-7f-5p expression level +0.202 9×miR-708-5p expression level -0.088 9×miR-135b-5p expression level +0.016 3×miR-100-5p expression level). ④ In the training cohort and the validation cohort, the overall survival rate of patients in the high-risk group was lower, and the difference was statistically significant (P<0.05) . The AUC of the prognosis-associated miRNA model for 1-, 3- and 5-year survival prediction was 0.640, 0.763 and 0.853, and was 0.631, 0.735 and 0.750 in validation cohort. ⑤Results of univariate analysis showed that age, tumor pathological stage, T stage, N stage, M stage and prognosis-associated miRNA model score were related factors for prognosis of gastric cancer patients (HR=1.017, 1.633, 1.353, 1.346, 2.652, 15.874; 95%CI 1.002?1.033, 1.333?2.001, 1.109?1.650, 1.169?1.548, 1.553?4.529, 5.729?43.985; P<0.05). Results of multivariate analysis showed that age, M stage and prognosis-associated miRNA model score were independent risk factors for prognosis of gastric cancer patients (HR=1.03, 2.27, 18.72; 95%CI 1.01?1.05, 1.09?4.70, 5.96?58.77; P<0.05). ⑥The AUC of the prognosis-associated miRNA model for 5-year survival prediction was 0.818 in 356 gastric cancer patients with complete clinicopathological data, higher than that of age, gender, tumor pathological stage, T stage, N stage, M stage and merged clinical factors. ⑦The results of Calibration curves, C-index, and DCA all indicated that patients with gastric cancer may get more net benefits from the prognostic nomogram than age, gender and tumor pathological stage.

    Conclusion

    ·A prognosis-associated miRNA prediction model that can be used to predict the survival of gastric cancer patients is constructed based on 5 miRNAs, which has a certain predictive ability to distinguish the survival status and prognosis of gastric cancer patients and can provide reference for clinical treatment.

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    Effects of different continuous infusion rates of cisatracurium on muscle relaxation and recovery of muscle relaxation during upper abdominal laparotomy
    Kai HE, Yan LUO, Chun-mei XU, Wei-fang JIN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 1125-1128.   DOI: 10.3969/j.issn.1674-8115.2021.08.022
    Abstract179)   HTML88)    PDF(pc) (866KB)(64)       Save
    Objective

    ·To investigate the effects of different continuous infusion rates of cisatracurium on muscle relaxation and recovery of muscle relaxation in upper abdominal laparotomy.

    Methods

    ·From January 2019 to January 2020, 60 patients scheduled for upper abdominal laparotomy in Shanghai Civil Aviation Hospital/Gubei Branch of Ruijin Hospital were randomly divided into low dosage [1.0 μg/(kg·min)] group (L group), middle dosage [1.5 μg/(kg·min)] group (M group) and high dosage [2.0 μg/(kg· min)] group (H group), according to the speed of intraoperative pump injection of cisatracurium, with 20 cases in each group. The amount of cisatracurium during the induction period, the cumulative pumping dosage during the operation, intraoperative muscle relaxation satisfaction, the time from drug withdrawal to the train of four stimulation (TOF) ratio recovery to 0.25, 0.75, 0.80 and 0.90 (TOFr 0.25, TOFr 0.75, TOFr 0.80, TOFr 0.90) and extubation time were recorded and compared among the three groups.

    Results

    ·There was no significant difference in the dosage of cisatracurium during induction among the three groups (P=0.662). The cumulative pump the dosage in the L group was lower than those in the M and H groups (P=0.025). There was no significant difference in intraoperative muscle relaxation satisfaction among the three groups (P=1.000). TOFr 0.25, TOFr 0.75, TOFr 0.80, TOFr 0.90 and extubation time in the L group were significantly shorter than those in the M and H groups (P=0.000), but there was no significant difference between M group and H group (P>0.05).

    Conclusion

    ·Continuous infusion of cisatracurium at the rate of 1.0 μg/(kg·min) during upper abdominal laparotomy can provide a good state of muscle relaxation. The increase of pump dosage can not significantly improve the effect of muscle relaxation, but can prolong the recovery time of muscle relaxation and extubation time.

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    Research progress in roles of follicular helper T cells in autoimmune diseases
    Xindi WEI, Xiaoyin NIU
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2022, 42 (2): 218-224.   DOI: 10.3969/j.issn.1674-8115.2022.02.013
    Abstract177)   HTML65)    PDF(pc) (1029KB)(67)       Save

    Follicular helper T cells (Tfh cells) have been defined as a new subset of CD4+ T cells in recent years, mainly expressing surface molecules such as C-X-C motif chemokine receptor type 5, inducible co-stimulator, and secreting cytokine interleukin-21, a key transcription factor of which is B cell lymphoma 6. They exist in the germinal center (GC) of lymphoid tissue and in the peripheral blood as well. With the ability to promote B cell maturation and differentiation, GC formation and antibody production, Tfh cells play important roles in the pathogenesis of many autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and primary Sj?gren's syndrome. The abnormal quantity and/or quality of Tfh cells will cause pathological processes like tissue injury and promote disease progression. This article reviews the biological characteristics of Tfh cells and their roles in different autoimmune diseases, which may help to further reveal the pathogenesis of certain autoimmune diseases and provide a new way to treat these diseases by targeting these cells.

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    Study on differentially expressed microRNA as a biomarker of polycystic ovary syndrome
    Yu-huan WANG, Yi-cen DING, Yao-yu CAI, Ya-ni KANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (11): 1429-1435.   DOI: 10.3969/j.issn.1674-8115.2021.11.005
    Abstract176)   HTML106)    PDF(pc) (2597KB)(63)       Save
    Objective

    ·To explore microRNAs (miRNAs) as biomarkers of polycystic ovary syndrome (PCOS) and the biological significance in the pathogenesis of PCOS.

    Methods

    ·Five patients with PCOS from January 2019 to October 2019 in Renji Hospital, Shanghai Jiao Tong University School of Medicine were selected as the observation group, and 5 healthy women were selected as the control group. Granulosa cells from 2 groups were collected and RNA was extracted by TRIzol method. TruSeq Small RNA Library Prep Kit was used to construct miRNA-Seq library. After the quality inspection of the library, NextSeq500 was used for high-throughput sequencing. Bioinformatics data analysis was performed on the sequencing results. RT-qPCR was used to verify the differential expression of candidate miRNA markers.

    Results

    ·We finally got 20 differentially expressed miRNAs (all P<0.05). Among them, miR-196a-5p, miR-10a-5p and miR-451a were significantly up-regulated, while miR-877-5p and miR-2355-5p were significantly down-regulated. These differentially expressed miRNAs and their target genes may be involved in the transcriptional regulation mechanism of PCOS occurrence and development.

    Conclusion

    ·Differentially expressed miRNAs have potential as PCOS biomarkers and are involved in the occurrence and development of PCOS.

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    Application progress of machine learning in the study of facial features of patients with depression
    Xin LI, Qing FAN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2022, 42 (1): 124-129.   DOI: 10.3969/j.issn.1674-8115.2022.01.019
    Abstract171)   HTML14)    PDF(pc) (832KB)(109)       Save

    Major depressive disorder (MDD) is a mental illness that severely affects the quality of life, accompanied by changes in facial expressions and other behaviors. The current diagnosis for MDD mainly relies on self-reports and observations from doctors, which has subjective errors. There is a lack of objective and effective automated MDD detection methods. Facial expressions are important nonverbal behaviors, and the researchers have begun to use facial features to assist in identifying and diagnosing depression. As the core of artificial intelligence, machine learning has outstanding advantages in image feature extraction and classification. Taking IEEE Xplore database as the data source, this article sorts out the researches on the facial features of MDD patients based on machine learning from 2016 to 2021, and prospects the future research directions, to provide reference for clinical intelligent diagnosis and tracking of MDD in the future.

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    Inhibition of CDDO-ME on ubiquitin-specific protease 2a activity and cell proliferation in triple negative breast cancer cells
    Yan-jie JI, Hao LUO, Hai-yan CAI, Xin-yu LIU, Shi-jia JIN, Shen-yue SU, Han-zhang XU, Hu LEI, Ying-li WU
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 1025-1032.   DOI: 10.3969/j.issn.1674-8115.2021.08.005
    Abstract169)   HTML29)    PDF(pc) (2591KB)(92)       Save
    Objective

    ·To explore the effect of bardoxolone methyl (CDDO-Me), an inhibitor of ubiquitin-specific protease 2a (USP2a) screened in vitro, on USP2a activity and cell proliferation in the triple negative breast cancer (TNBC) cells.

    Methods

    ·Ubiquitin-specific protease inhibitor screening system was used to screen USP2a inhibitors and CDDO-Me was obtained. Molecular docking technology was used to analyze the interaction of CDDO-Me and USP2a. Cellular thermal shift assay (CETSA) was used to detect the interaction between CDDO-Me and USP2a protein in three TNBC cell lines. Western blotting was used to detect the changes of USP2a substrates including β-catenin and tumor necrosis factor receptor-associated factor 6 (TRAF6) protein levels and apoptosis-related proteins including caspase3 and poly (ADP-ribose) polymerase 1 (PARP1). Cell counting kit-8 (CCK8) was used to detect the effect of CDDO-Me on the proliferation of TNBC cells. MDA-MB-468 cells were transiently transfected with pLVX (pLVX group) or pLVX-USP2a (pLVX-USP2a group) plasmids. After CDDO-Me treatment, the protein levels of β-catenin and TRAF6 were detected by Western blotting, the cell cycle was detected by flow cytometry, and the number of viable cells was detected by trypan blue exclusion method.

    Results

    ·CDDO-Me inhibited the activity of USP2a in vitro, and half-maximal inhibitory concentration was 3.84 μmol/L. The results of molecular docking analysis showed that CDDO-Me formed a hydrogen bond with His456 residue of USP2a, and had hydrophobic interactions with Phe409 and Tyr514 residues. CETSA results showed that CDDO-Me binded to the USP2a protein in the three TNBC cells. The results of Western blotting showed that CDDO-Me down-regulated the protein levels of β-catenin and TRAF6, while the two USP2a substrates did not decrease in the USP2a-overexpressed MDA-MB-468 cells treated by the same concentration of CDDO-Me. CDDO-Me inhibited the proliferation of TNBC cells in a dose-dependent manner, caused caspase3 activation and PARP1 cleavage, and led to S phase and G2/M phase arrest. Compared with the pLVX group, there were more viable cells in the pLVX-USP2a group and the cells also did not undergo cycle arrest.

    Conclusion

    ·CDDO-Me can inhibit the activity of USP2a in TNBC cells, inhibit the proliferation of TNBC cells and induce apoptosis.

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    In vitro screening and validation of novel targeted therapeutic strategy against diffuse intrinsic pontine glioma
    Rui LI, Yu-jie HAN, Lei ZHANG, Yu-jie TANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (8): 987-998.   DOI: 10.3969/j.issn.1674-8115.2021.08.001
    Abstract168)   HTML25)    PDF(pc) (13331KB)(73)       Save
    Objective

    ·To find and identify new targeted therapeutic compounds and combinations for diffuse intrinsic pontine glioma (DIPG) from the perspective of epigenetics.

    Methods

    ·Selection of small molecule compounds was based on the previously published transcriptome analysis of 8 cases of DIPG and 6 cases of normal brain tissues. New inhibitory compounds of DIPG were identified by single agent screening in DIPG primary tumor cells. The changes of target genes at mRNA and protein expression level were detected by real-time PCR and Western blotting after drug treatment. The effects of drug treatment on the proliferation and apoptosis of DIPG primary tumor cells were detected by FACS analyses after EdU and Annexin V/propidium iodide staining, respectively. The combinatory screening of small molecular compounds was performed with bromodomain and extra terminal protein (BET) inhibitor JQ1 or histone deacetylase (HDAC) inhibitor panobinostat, and the drug combination with inhibitory effect on DIPG was verified in vitro.

    Results

    ·Sixty-six small molecules were chosen to be applied to screening. Single agent screening identified that YM155 could significantly inhibit DIPG primary tumor cell growth, and BIRC5 (baculoviral IAP repeat containing 5; gene encoding survivin), a target gene of YM155, was significantly upregulated in DIPG tumor tissues (P=0.018). YM155 could reduce the expression of BICR5 at both mRNA and protein levels. YM155 could repress proliferation and induce apoptosis of DIPG. CX4945 and ABT-737 from the targeted small molecular library were combined with JQ1 (BET inhibitor) and panobinostat (HDAC inhibitor), respectively,which could synergistically inhibit the activity of DIPG cells in vitro.

    Conclusion

    ·Novel targeted therapeutic strategies for DIPG has been identified through single drug and combination drug screening, providing basis for further validation in vivo and therapeutic mechanism exploration.

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    Screening potential hub genes associated with myocardial ischemia-reperfusion injury in mice based on GEO database and bioinformatics analysis
    Jianru WANG, Guangcao PENG, Mingjun ZHU
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2022, 42 (1): 51-62.   DOI: 10.3969/j.issn.1674-8115.2022.01.008
    Abstract168)   HTML24)    PDF(pc) (8936KB)(173)       Save
    Objective

    ·To screen the potential hub genes associated with myocardial ischemia-reperfusion injury (MIRI) in mice by bioinformatics analysis based on gene expression omnibus (GEO) database.

    Methods

    ·The mouse MIRI data sets GSE61592, GSE83472 and GSE160516 were obtained from GEO database. The differentially expressed genes (DEGs) in each data set were screened by limma package, and then robust DEGs were screened by robust sorting integration (RRA) method. The protein-protein interaction (PPI) network of robust DEGs was constructed, and the submodules and hub genes in the PPI network were screened. The clusterProfiler package was used to analyze the robust DEGs, the most important submodule genes and hub genes by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Eighteen male C57BL/6 J mice aged 6?8 weeks were randomly divided into sham group and MIRI group, 9 mice each group. The MIRI model was constructed by left anterior descending coronary artery ligation for 30 min ischemia and 24 h reperfusion, and the mRNA expression of hub genes was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

    Results

    ·RRA method identified 294 robust DEGs in three data sets. In PPI network, a total of 14 sub-modules were screened, of which module 1 was the most important and 17 hub genes were found. GO and KEGG analysis showed that the robust DEGs, module 1 genes, and the hub genes were mainly involved in regulating the migration of inflammatory cells, the activity of chemokines and cytokines and their receptors, Toll-like receptors and other biological function and signaling pathways. RT-qPCR results showed that compared with the sham group, the expressions of chemokine (C-C motif) ligand 4 (Ccl4), Ccl6, Ccl7, chemokine (C-X-C motif) receptor 4 (Cxcr4), chemokine (C-C motif) receptor 2 (Ccr2), signal-regulatory protein β1 (Sirpb1), low affinity immunoglobulin gamma Fc region receptor Ⅱb (Fcgr2b), leukocyte surface antigen CD53 (Cd53), arachidonate 5-lipoxygenase activating protein (Alox5ap), myeloid differentiation primary response gene 88 (Myd88), macrophage scavenger receptor 1 (Msr1), matrix metallopeptidase 14 (Mmp14), triggering receptor expressed on myeloid cells 2 (Trem2) and leupaxin (Lpxn) were up-regulated in the myocardium of the MIRI group, but there was no difference in low affinity immunoglobulin gamma Fc region receptor Ⅲ (Fcgr3), complement C1q subcomponent subunit B (C1qb) and a disintegrin and metalloproteinase domain-containing protein 8 (Adam8). By reviewing the literatures, Trem2, Lpxn, Cd53, Alox5ap, Sirpb1 and Fcgr2b were not reported to participate in MIRI.

    Conclusion

    ·This study has unearthed 6 potential hub genes for MIRI in mice, and the results can provide new ideas and entry points for further exploring the molecular mechanism and therapeutic targets of MIRI.

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