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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
    Abstract259)   HTML14)    PDF(pc) (908KB)(144)       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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    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
    Abstract250)   HTML30)    PDF(pc) (4693KB)(128)       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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    Clinical characteristics and prognosis of pediatric acute leukemia patients with MLL gene rearrangements
    Qing LIU, Na ZHANG, Jing-bo SHAO, Hong LI, Kai CHEN, Cheng-kan DU, Zhen WANG, Hui JIANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (7): 903-909.   DOI: 10.3969/j.issn.1674-8115.2021.07.009
    Abstract205)   HTML12)    PDF(pc) (1094KB)(68)       Save
    Objective

    ·To analyze the clinical characteristics and prognosis of pediatric acute leukemia (AL) patients with positive mixed linage leukemia (MLL) gene rearrangement (MLL-r).

    Methods

    ·Forty-five children with MLL-r AL admitted to Shanghai Children′s Hospital, Shanghai Jiao Tong University from January 1, 2009 to December 31, 2019 were retrospectively analyzed. Fluorescence in situ hybridization and/or fluorescent real-time PCR were used to detect the MLL-r. Kaplan-Meier method was used to evaluate the survival of children. Log-rank test was used to compare the difference of survival rate. Univariate analysis and multivariate analysis were performed on the factors influencing survival, such as gender, age and the number of white blood cells.

    Results

    ·The incidence rate of MLL-r in children with AL in our center was 7.1%, and the incidence rate of MLL-r in children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were 5.4% and 13.3%, respectively. The difference between the two groups was statistically significant (P=0.002). The age of the two groups of children (>1 year and ≤1 year) and the number of white blood cells at the time of onset (≥50×109/L and <50×109/L) were compared. The differences were statistically significant (P=0.032 and 0.021). The main immunophenotype of children with MLL-r ALL was early precursor B-ALL, accounting for 79.2%. The main immunophenotype of children with MLL-r AML was M5, accounting for 77.8%. MLL partner gene analysis showed that MLL/AF4 accounted for 59.2% (16/27) of MLL-r ALL children, of which 68.7% (11/16) were children younger than 1 year old. Compared with the children younger than 1 year old in the non-MLL/AF4 group, the difference was statistically significant (P=0.034). The majority of children with MLL-r AML were MLL/AF9, accounting for 33.3%. Of the 45 patients, 42 cases were included for the prognosis analysis. The complete remission rate was 97.6% (41/42), and the median follow-up time was 26 (2?138) months. The median event-free survival (EFS) and overall survival (OS) time were 21 months and 24.5 months, respectively. The 3-year EFS and OS rates were (41.8±9.4) % and (60.9±9.3) %, respectively. The median duration of EFS and OS in children with MLL-r ALL were 21.5 months and 28 months, respectively, and the 3-year EFS and OS rates were (44.3±11.7) % and (58.2±12.1) %, respectively. The median EFS and OS time in children with MLL-r AML were 16 months and 23 months, respectively. The 2-year EFS and OS rates were (36.5±15.8) % and (64.7±14.5) %, respectively. Eight cases of ALL children relapsed, with a median recurrence time of 20 (2?36) months; 7 cases of AML children relapsed, with a median recurrence time of 16 (5?38) months, and the cumulative recurrence rates were 48.4% and 63.9%, respectively. There was no statistically significant difference between them (P=0.398). Univariate analysis showed that between the groups of MLL-r ALL children >1 year and ≤1 year, white blood cell count ≥50×109/L and <50×109/L, platelet count ≥30×109/L and <30×109/L, there were statistically significant differences in the EFS rate. The P values were 0.028, 0.024 and 0.027 respectively. Multivariate analysis showed that the number of white blood cells at onset was an independent prognostic factor affecting EFS in children with MLL-r ALL (RR=6.113, 95% CI 0.017?1.050, P=0.013).

    Conclusion

    ·The incidence of MLL-r in children with AML is higher than that in children with ALL. The main immunophenotype of MLL-r ALL is early precursor B-ALL. The main immunophenotype of MLL-r AML is M5. Conventional chemotherapy produces a high response rate, which is likely to relapse. The number of white blood cells at the onset ≥50×109/L is a poor prognostic factor for children with MLL-r ALL.

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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
    Abstract183)   HTML120)    PDF(pc) (917KB)(85)       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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    Suppressing effect of the Na +/Ca 2+ exchanger blocker CB-DMB on the growth of human glioblastoma cells
    Jing-jing LIU, Hui-jie HU, Zi-kai LIU, Ming-ke SONG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 710-716.   DOI: 10.3969/j.issn.1674-8115.2021.06.002
    Abstract182)   HTML168)    PDF(pc) (2296KB)(49)       Save
    Objective

    ·To test the inhibitory effect of the Na+/Ca2+ exchanger (NCX) blockers on the growth of human glioblastoma cells.

    Methods

    ·Human glioblastoma cell lines (U87, U251 and SF188) and human astrocytes were cultured in vitro. The cells were treated with NCX blockers SN-6, YM244769, SEA0400, CB-DMB and the chemotherapeutic agent temozolomide (TMZ). SN-6, YM244769 and SEA0400 were selective inhibitors for the reverse operation of NCX; while CB-DMB was NCX bidirectional blocker, but preferentially blocked the forward mode of NCX. The TMZ was used as a reference drug. Cell counting kit-8 (CCK-8) assay was used to quantify and assess the cell viability, and half maximal inhibitory concentration (IC50) of the drug was obtained. Calcium imaging was used to detect the changes of Ca2+ signal in U87 cells treated with NCX inhibitors, and Western blotting was used to detect the expression of mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cellular apoptosis was evaluated by flow cytometry assay.

    Results

    ·CCK-8 results showed that direct application of the NCX bidirectional blocker CB-DMB to glioblastoma cell lines (U87, U251 and SF188) for 48 h caused a dose-dependent growth inhibition with IC50 values of 2.06, 2.19 and 1.82 μmol/L, respectively. In contrast, NCX reverse blockers SN-6, YM244769 and SEA0400 had no significant effect on the growth activity of glioblastoma cells. CB-DMB had little effect on the growth activity of human astrocytes. Calcium imaging and Western blotting results confirmed that CB-DMB blocked the forward transport mode of NCX to elevate intracellular Ca2+, causing intracellular calcium overload and then inducing apoptosis of U87 cells and activating MAPK signaling pathway. Flow cytometry assay results showed that the rate of apoptosis induced by CB-DMB in glioblastoma cells was much faster than that induced by TMZ (P=0.002). The combination of CB-DMB and TMZ enhanced the inhibitory effect of TMZ on the growth of tumor cells.

    Conclusion

    ·The inhibitory effect of CB-DMB on the growth of human glioblastoma cells may be related to blocking the forward transport mode of NCX. The plasma membrane NCX is a potential new target for the treatment of human glioblastoma.

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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
    Abstract174)   HTML29)    PDF(pc) (4390KB)(107)       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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    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
    Abstract161)      PDF(pc) (5369KB)(87)       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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    Observation of therapeutic efficacy of metformin on glucose dysregulation and dyslipidaemia induced by quetiapine in patients with schizophrenia
    Bing-fu SONG, Bin-bin Ding, Xiao-li ZHANG, Li-yun YAO
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 776-780.   DOI: 10.3969/j.issn.1674-8115.2021.06.012
    Abstract161)   HTML7)    PDF(pc) (1347KB)(62)       Save
    Objective

    ·To investigate the therapeutic efficacy of metformin (MF) on glucose dysregulation and dyslipidaemia induced by quetiapine in patients with schizophrenia (SZ).

    Methods

    ·A total of 83 SZ patients from Shanghai Hongkou District Mental Health Center and Shanghai Yangpu District Mental Health Center were enrolled, and randomly divided into treatment group (MF group, n=38) and control group (n=45). The control group received oral quetiapine therapy, and the MF group additionally received metformin on the basis of oral quetiapine therapy. The serum levels of glucose (GLU), total cholesterol (TC), triacylglycerol (TAG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), small density low-density lipoprotein cholesterol (sd-LDL-C) and homocysteine (HCY) were determined before treatment and 2, 4 and 8 weeks after treatment.

    Results

    ·There were no statistic differences in ages, courses, body mass index, the levels of GLU, TC, TAG, HDL-C, LDL-C, sd-LDL-C and HCY between the control and MF group before treatment (all P>0.05). After 8 weeks of treatment, levels of all biomarkers elevated in the control group. The levels of GLU, TC, TAG, LDL-C, sd-LDL-C and HCY were lower after treatment, and the level of HDL-C elevated higher in the MF group. The variations of levels of HDL-C after treatment showed statistically no significant difference between the two groups (P=0.247), while statistical differences existed in other biomarkers, which indicated that the glucose-lowering and lipid-lowering efficacies in the MF group were significantly better than those in the control group. The analysis of variance suggested that, in the control group, the level of HDL-C elevated significantly after 4 and 8 weeks′ treatment, having statistical differences (P=0.005 and P=0.003). The level of LDL-C elevated significantly after 2, 4 and 8 weeks′ treatment (P=0.005, P=0.019 and P=0.026), and no statistical differences were observed in other biomarkers. In the MF group, the levels of GLU, TC, TAG and sd-LDL-C were lower 2, 4 and 8 weeks after treatment, the levels of LDL-C and HCY descended 4 and 8 weeks after treatment, and no statistical differences were observed in other biomarkers. The level of HDL-C was higher after 2 weeks, treatment, but showed statistically no significant differences 4 and 8 weeks after treatment, compared to the level determined before treatment.

    Conclusion

    ·Administration of MF in the SZ patients having glucose dysregulation and dyslipidaemia induced by quetiapine can significantly lower serum level of GLU, and improve the serum lipid profiles.

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    Validity and reliability of the Chinese version of Defeat Scale in men who have sex with men
    Shang-bin LIU, Hao YANG, Chen XU, Jing-wen DONG, Xiao-yue YU, Yong CAI, Dong YUAN, Ying WANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 793-798.   DOI: 10.3969/j.issn.1674-8115.2021.06.015
    Abstract159)   HTML3)    PDF(pc) (1456KB)(36)       Save
    Objective

    ·To test the reliability and validity of the Chinese version of Defeat Scale (DS) in the men who have sex with men (MSM) in Shanghai and Shenyang, China, and explore its value in judging the depressive state of the population.

    Methods

    ·A cross-sectional survey was conducted among 530 men over the age of 18 who had made sex with men in the past 6 months in Shanghai and Shenyang. DS and Patient Health Questionnaire-9 (PHQ-9) were used. Excel 2010 was used to establish the database, and SPSS 23.0 and Amos 25.0 software were used to analyze the reliability and validity of the data. Shapiro-Wilk test was used to determine whether the data obeyed normal distribution. Exploratory factor analysis and confirmatory factor analysis were used to verify its structural validity of DS. Spearman correlation coefficient was conducted to evaluate the content validity. Cronbach's α coefficient and Spearman-Brown coefficient were used to evaluate the reliability of DS. Binary Logistic regression was used to determine whether defeat can affect depression, and then, receiver operator characteristic (ROC) curve was used to determine its diagnostic value.

    Results

    ·The data of DS and PHQ-9 did not obey the normal distribution. The exploratory factor analysis showed that two factors including decadence (13 items) and low sense of achievement (3 items) could be extracted. Explained variance of the scale was 69.35%. The confirmatory factor analysis showed that each item of the revised two-factor model was greater than 0.50, and the minimum value was 0.52. The model fitted well [ χ2/df =3.430<5; root mean square error of approximation (RMSEA)= 0.068, standardized root mean square residual (SRMR)=0.043, all<0.080; normed fit index (NFI)=0.944, incremental fit index (IFI)=0.959, comparative fit index (CFI)=0.959, goodness of fit index (GFI)=0.909, Tucker-Lewis Index (TLI)=0.958, all>0.900]. The Cronbach's α coefficient of DS of the 16 items was 0.934, and the Cronbach's α of two dimensions, namely "decadence" and "low achievement" were 0.962 and 0.758, respectively. With depression as the dependent variable and DS score as the covariant, binary Logistic regression was carried out. The results showed that β value was 0.178, P=0.000. Odds ratio (OR) value was 1.195 and 95% confidence interval (CI) was 1.147-1.245. The area under the curve (AUC) was 0.891, P=0.000. The maximum Youden index value was 0.667, its corresponding DS score was 21.5, and its sensitivity and specificity were 87.0% and 80.7%, respectively.

    Conclusion

    ·The Chinese version of DS has good reliability and validity in MSM, and also has the value in judging the state of depression in this population.

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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
    Abstract157)   HTML15)    PDF(pc) (867KB)(69)       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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    Exploratory study on downregulation of PD-L1 in KRAS G12V-mutant non-small cell lung cancer cells by selumetinib
    Yun-fang MA, Li-na PAN, Zhen LI, Bei-li GAO, Jia-an HU, Zhi-hong XU
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 741-748.   DOI: 10.3969/j.issn.1674-8115.2021.06.006
    Abstract155)   HTML5)    PDF(pc) (3442KB)(53)       Save
    Objective

    ·To investigate the correlation between Kirsten rat sarcoma viral oncogene (KRAS)-mutant subtypes and programmed cell death ligand 1 (PD-L1) expression in the non-small cell lung cancer (NSCLC) tissues and cell lines, and the possible underlying mechanism.

    Methods

    ·Real-time quantitative PCR and fluorescence-activated cell sorting were used to verify the correlation between PD-L1 mRNA or protein and KRAS mutation status in the NSCLC cell lines. Immunohistochemistry was used to detect the expression of PD-L1 in the tumor tissues of 77 NSCLC patients with early stages (Ⅰa?Ⅱb). The effect of KRAS mutation on the cytokines in the RAS downstream signaling pathway, i.e., protein kinase B (PKB or AKT), mammalian target of rapamycin (mTOR), ribosomal S6 protein kinase (p70S6K), and extracellular regulated protein kinase (ERK), was studied by Western blotting. Dabrafenib (RAF inhibitor), selumetinib [mitogen activated-protein kinase (MEK) inhibitor], GDC0941 (phosphoinositide 3-kinase inhibitor), MK2206 (AKT inhibitor), and rapamycin (mTOR inhibitor) were used to treat 6 KRAS-mutant cell lines, respectively, to detect the regulation of these five tyrosine kinase inhibitors on PD-L1 expression.

    Results

    ·In the NSCLC cell lines, the expressions of PD-L1 mRNA and protein in the KRAS mutant cell lines were significantly higher than those in the KARS wild-type cell lines (P<0.05). KRAS G12V- and G12C-mutant cell lines showed the highest expression of PD-L1 mRNA and protein, respectively. For the NSCLC patients with early stages, the proportions of PD-L1 overexpression in the tumor tissues of the patients with KRAS G12V and G12D mutants were significantly higher than those of the patients with KRAS wild-type. Western blotting showed that in the KRAS-mutated NSCLC cell lines, p70S6K was activated, while ERK, AKT and mTOR were not activated. Moreover, 1 μmol/L GDC0941, 0.5 μmol/L MK2206, and 10 nmol/L rapamycin could not affect the expression of PD-L1 in the 6 KRAS-mutant cell lines. Darafenib (5 nmol/L) up-regulated PD-L1 in only one KRAS G12V-mutant cell line and one L19F-mutant cell line (P<0.05), while selumetinib (0.1 μmol/L ) inhibited the expressions of PD-L1 in three KRAS G12V-mutant cell lines and one L19F-mutant cell line (P<0.05) in a dose-dependent manner.

    Conclusion

    ·The expressions of PD-L1 in the tumor tissues and cell lines of NSCLC with KRAS mutation, especially G12V mutation subtype, were higher than those in the NSCLC tissues and cell lines with KRAS wild-type. Selumetinib can downregulate the expression of PD-L1 in KRAS G12V-mutant NSCLC cells, which suggests that KRAS G12V-mutant NSCLC cells may up-regulate the expression of PD-L1 by upregulating MEK.

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    Influence of obsessive beliefs and impulsivity traits on symptom dimensions of obsessive-compulsive disorder patients
    Pu-yu LI, Jia-yue CHENG, Qiu-meng GU, Han-yang RUAN, Yong WANG, Qiang LIU, Yan-ru WU, Zhen WANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 756-760.   DOI: 10.3969/j.issn.1674-8115.2021.06.008
    Abstract155)   HTML4)    PDF(pc) (1120KB)(63)       Save
    Objective

    ·To test the effects of obsessive beliefs and impulsivity traits on different subtypes of obsessive-compulsive (OCD).

    Methods

    ·A total of 139 non-medicated OCD patients and 110 matched healthy controls (HCs) were enrolled. The clinical symptoms were evaluated separately using Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Obsessive Beliefs Questionnaire-44 (OBQ-44), Barratt Impulsiveness Scale (BIS-11), and Obsessive Compulsive Inventory-Revised (OCI-R). Multiple linear regression analysis was used to evaluate the influence of obsessive beliefs and impulsive traits on symptom dimensions of obsessive-compulsive disorder.

    Results

    ·The scores of all clinical scales of OCD patients were significantly higher than those of HCs (P<0.05). Obtained by multiple regression, the checking score was affected by responsibility/threat estimate (RT) and motor impulsiveness (MI) (B=0.053, P=0.00; B=-2.000, P=0.011); the ordering score was significantly affected by the perfectionism/certainty (PC) belief (B=0.049, P=0.001); the score of obsessing was affected by the belief in RT (B=0.082, P=0.000); the neutralizing score was affected by both RT belief and cognitive impulsiveness (CI) (B=0.038, P=0.006; B=0.248, P=0.044).

    Conclusion

    ·OCD patients with different obsessive-compulsive beliefs and impulsivity traits will conduct different symptoms.

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    Effect of positive end-expiratory pressure on the incidence of atelectasis in children with congenital heart disease undergoing lateral thoracotomy under cardiopulmonary bypass
    Pan HE, Ying SUN, Yan-yan YANG, Jie BAI, Ji-jian ZHENG, Ma-zhong ZHANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 781-785.   DOI: 10.3969/j.issn.1674-8115.2021.06.013
    Abstract154)   HTML4)    PDF(pc) (1537KB)(40)       Save
    Objective

    ·To evaluate the incidence of atelectasis in children undergoing lateral thoracotomy cardiac surgery with cardiopulmonary bypass (CPB) by lung ultrasound, and investigate the effect of positive end-expiratory pressure (PEEP) on the incidence of atelectasis in these children.

    Methods

    ·Sixty children undergoing selective lateral thoracotomy cardiac surgery with CPB in Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from October 2019 to August 2020 were included. They were randomly divided into PEEP group (P group, n=30) and control group (C group, n=30). The P group was treated with 5 cmH2O PEEP immediately after tracheal intubation until the end of operation. The C group was treated with 5 cmH2O PEEP immediately after tracheal intubation until the beginning of operation. Lung ultrasound exam was performed three times in each patient, 1 min after starting mechanical ventilation of the lungs (T1), 1 min before the beginning of surgery (T2) and the time immediately upon completion of the surgery (T3). The lung ultrasound scores of the two groups were recorded, and the incidences of atelectasis were compared.

    Results

    ·There was no significant difference in the incidences of atelectasis at T1 and T2 between the two groups. The incidence of atelectasis in P group was significantly lower than that in the C group at T3 (P=0.000). The incidence of atelectasis in the C group at T3 was significantly lower than those at T1 and T2 (all P<0.05).

    Conclusion

    ·PEEP can significantly reduce the incidence of atelectasis in children undergoing lateral thoracotomy cardiac surgery with CPB.

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    A clinical study on treatment failure of childhood acute lymphoblastic leukemia
    Jia-shi ZHU, Hong LI, Jing-bo SHAO, Na ZHANG, Jing-wei YANG, Kai CHEN, Zhen WANG, Hui JIANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 764-769.   DOI: 10.3969/j.issn.1674-8115.2021.06.010
    Abstract154)   HTML5)    PDF(pc) (1386KB)(62)       Save
    Objective

    ·To analyze the reasons for the treatment failure of childhood acute lymphoblastic leukemia (ALL), and explore the strategy in failure reduction.

    Methods

    ·A retrospective study was conducted on the cases with treatment failure in 330 children who were initially diagnosed as having ALL in Shanghai Children's Hospital from January 2006 to June 2017 to analyze the reasons for failure. The clinical characteristics of the children with different reasons were analyzed respectively. Kaplan-Meier survival curve analysis and COX regression model were used to explore the recurrence rate, overall survival (OS) rate and risk factors of recurrence. The difference of the stages of infection occurrence in the children with different risk levels was explored by χ2 test.

    Results

    ·Among the 330 children with ALL, 84 cases failed in treatment. The reasons for treatment failure included disease recurrence (58 cases), death due to severe infection (19 cases), second tumor occurrence (2 cases), and death from other causes (5 cases). Totally 58 ALL children relapsed, whose median recurrence time was 27 (2-95) months. The 5-year cumulative recurrence rate was (18.2 ± 2.3)%, and the 10-year cumulative recurrence rate was (22.4 ± 2.9)%. Multivariate analysis showed that poor treatment response in the early stage (HR=5.43, P=0.000) and medium and high risk of disease (HR=2.26, P=0.017) were independent risk factors for recurrence. According to the recurrence time, the 5-year OS rate of children with very early recurrence was (16.7±10.2)%, significantly lower than that of children with early and late recurrence (P=0.000). According to the location of recurrence, the 5-year OS rate of children with simple bone marrow recurrence was (42.0±10.2)%, significantly lower than that of children with simple extramedullary recurrence (P=0.044). Of the 55 children with severe infection, 26 cases had sepsis, 20 cases had respiratory infection with acute respiratory distress syndrome, and 9 cases had severe intestinal infection. There were statistically significant differences in the stage distribution of infection occurrence in the children with different risk levels (P=0.019). Low-risk children were more likely to have serious infection during the induction and consolidation treatment phase (P=0.022), and medium-and-high-risk children were more likely to have serious infection in the mid-stage of intensive treatment (P=0.044).

    Conclusion

    ·Recurrence and death from infection are the main causes for treatment failure in childhood ALL. Active prevention and treatment of very early recurrence and infection can reduce the incidence of treatment failure and improve the long-term survival rate of the children.

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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
    Abstract154)   HTML26)    PDF(pc) (3871KB)(55)       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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    Function of branched-chain amino acid catabolism in lung cancer cells
    Yan-qi HE, Rui CHI, Meng-ping CHEN, Si CHEN, Chun-liang LIU, Yun-xia LIU, Hai-peng SUN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (7): 858-864.   DOI: 10.3969/j.issn.1674-8115.2021.07.003
    Abstract153)   HTML17)    PDF(pc) (1757KB)(25)       Save
    Objective

    ·To explore the function and mechanism of branched-chain amino acid (BCAA) catabolism in lung cancer cells.

    Methods

    ·Small interfering negative control (siNC) and small interfering branched-chain keto acid dehydrogenase kinase (siBCKDK) were transfected into non-small cell lung cancer cells H1299, A549 and HCC827 by instantaneous transfection. The expression of BCKDK, branched-chain keto acid dehydrogenase e1, α polypeptide (BCKDE1α) and its phosphorylation in siNC group and siBCKDK group were detected by Western blotting. The proliferation activity of the above two groups of cells was detected by CCK-8 assay. The above three kinds of cells were cultured in culture medium containing 0, 100, 200 μmol/L BT2 (3, 6-dichlorobenzo[b]thiophene-2-carboxylic acid), respectively. The expression of BCKDE1α and its phosphorylation were detected by Western blotting. The proliferation activity of 0 μmol/L BT2 group and 200 μmol/L BT2 group was detected by CCK-8 assay. The cell viability of siNC group and siBCKDK group, 0 μmol/L BT2 group and 200 μmol/L BT2 group in H1299 and A549 cells was calculated by trypan blue staining. Cell number at different phases of cell cycle was detected by propidium iodide staining. Cyclin-dependent kinase inhibitor 1A (P21) expression was detected by Western blotting.

    Results

    ·In H1299, A549 and HCC827 cells, compared with siNC group, expression of BCKDK and phosphorylation of BCKDE1α in siBCKDK group were down-regulated, and the proliferation activity was decreased (all P=0.000). Compared with 0 μmol/L BT2 group, the phosphorylation of BCKDE1α was down-regulated in H1299, A549 and HCC827 cells in both 100 μmol/L BT2 group and 200 μmol/L BT2 group, but more obviously in 200 μmol/L BT2 group. The cell proliferation activity in 200 μmol/L BT2 group was decreased compared with that in 0 μmol/L BT2 group (all P=0.000). There was no significant difference in the cell viability of H1299 and A549 cells between siBCKDK group and siNC group, 200 μmol/L BT2 group and 0 μmol/L BT2 group, but G0/G1 cell cycle arrest occurred (all P<0.05) with the expression of P21 increasing.

    Conclusion

    ·siBCKDK and BT2 can promote the dephosphorylation of BCKDE1α and accelerate the catabolism of BCAA, which may inhibit the proliferation of lung cancer cells by up-regulating P21 and blocking cell cycle.

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    Identification of differentially expressed gene modules in major depressive disorder based on weighted gene co-expression network analysis
    Rui-jie GENG, Lin YAO, Xin-xin HUANG, Shun-ying YU, Cheng-mei YUAN, Wu HONG, Qin-yu LÜ, Qing-zhong WANG, Zheng-hui YI, Yi-ru FANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 724-731.   DOI: 10.3969/j.issn.1674-8115.2021.06.004
    Abstract152)   HTML11)    PDF(pc) (5613KB)(98)       Save
    Objective

    ·To explore the differential gene modules and hub genes of major depressive disorder (MDD) by weighted gene co-expression network analysis (WGCNA), and annotate the biological functions of the differential gene modules.

    Methods

    ·Based on the previous experiment of peripheral blood mRNA microarray analysis of 8 MDD patients and 8 healthy controls (control group), t-test statistical method was used to screen the differentially expressed genes between MDD and the control group. WGCNA package in R software was used to analyze the weighted gene co-expression network. The correlation coefficient threshold was set to 0.9 with β =14 to construct the co-expression network of the gene dataset. The hybrid dynamic tree cutting method was used to cut the network to generate gene modules. Pearson correlation test was used to evaluate the correlation between gene modules and MDD. The gene modules with the strongest positive correlation and the strongest negative correlation with depression were selected respectively, and the top three genes with the highest connectivity in the modules were defined as hub genes. Finally, GO functional enrichment analysis and KEGG pathway analysis were used to annotate the functions of the two modules.

    Results

    ·A total of 4 125 differentially expressed genes were obtained from 16 samples, and 9 gene modules were identified. The blue module (R=-0.91, P=0.000) and the cyan module (R=0.76, P=0.000) were selected for further study. The hub genes of blue module were JAM2 (junctional adhesion molecule 2), SCRN2 (secernin 2) and IGHV7-81 (immunoglobulin heavy variable 7-81). The hub genes of cyan module were SCFD2 (Sec1 family domain containing 2), NR5A2 (nuclear receptor subfamily 5 group A member 2) and KCNMA1 (potassium calcium-activated channel subfamily M alpha 1). It was found in the annotation of biological function that the genes of the cyan module were mainly enriched in the embryo development, cell growth and immune and inflammatory response, while the genes of the blue module were mainly enriched in material processing and transport and infection.

    Conclusion

    ·Two peripheral blood mRNA gene modules and six hub genes (JAM2, SCRN2, IGHV7-81, SCFD2, NR5A2 and KCNMA1) may be significantly associated with MDD. These two gene modules may play a role in the embryonic development, immune and inflammatory response, and material processing and transportation.

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    Screening of key genes and pathways involved in lupus nephritis based on GEO database
    Yin LIU, Tao YANG, Yu-sai XIE, Yu-zhu WANG
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (6): 749-755.   DOI: 10.3969/j.issn.1674-8115.2021.06.007
    Abstract150)   HTML9)    PDF(pc) (5461KB)(58)       Save
    Objective

    ·To identify the differentially expressed genes and pathways involved in lupus nephritis (LN) using bioinformatics analysis.

    Methods

    ·The matrix data of GSE32591 dataset was downloaded from the GEO database, and the limma package of R software was applied to standardize and screen the differentially expressed genes. The volcano map and heatmap of the differentially expressed genes were drawn by ggpubr and pheatmap packages. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes were performed using DAVID online database, and bar plot and bubble chart were drawn using R software ggplot package. STRING database and Cytoscape software were used to construct protein interaction networks of differentially expressed genes, and MCODE and cytohubba plug-ins were used to screen out the most significant modules and key genes involved in lupus nephritis. GSE99339 dataset was used to verify the differential expression of hub genes.

    Results

    ·The GSE32591 data set was analyzed through the limma package, and 367 differentially expressed genes were obtained, including 253 up-regulated genes and 114 down-regulated genes. GO analysis and KEGG pathway enrichment analysis showed that differentially expressed genes were significantly enriched in virus defense response, cytoplasmic matrix, influenza A, tuberculosis, EB virus infection, complement pathway, etc. A protein interaction network of differentially expressed genes was constructed by STRING and Cytoscape, and 10 pivotal genes related to LN were identified. The hub genes are significantly differentially expressed in the GSE99339 validation dataset.

    Conclusion

    ·The 367 differentially expressed genes and 10 hub genes are potential biomarkers of LN.

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    Preparation of cell membrane-coated nanoparticles and its application to antimicrobial
    Ting-wang SHI, Yun-feng CHEN
    JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)    2021, 41 (7): 953-958.   DOI: 10.3969/j.issn.1674-8115.2021.07.017
    Abstract150)   HTML1)    PDF(pc) (1598KB)(86)       Save

    Due to the complex pathophysiological characteristics of the infected microenvironment and the development of bacterial resistance, conventional antibiotic treatments are facing increasingly more clinical challenges. Cell membrane-coated nanoparticle (CMCNP) is a kind of biomimetic materials emerging in recent years which can be obtained by directly wrapping the membrane vesicles onto the nanoparticle cores through physical means. Recently, CMCNP has displayed a wide application prospect in the areas of targeting infected areas, neutralization of bacterial toxins and development of antibacterial vaccines with the help of biological functions of cell membrane vesicles and the superior physicochemical properties of nanoparticles. However, CMCNP is still at the experimental stage in the biomedical field, and its safety and effectiveness need to be further verified for clinical applications.

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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
    Abstract148)   HTML9)    PDF(pc) (991KB)(71)       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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