Journal of Shanghai Jiao Tong University (Medical Science)

Construction of translocase of inner mitochondrial membrane 8A gene knockout mice and study of its inner ear function

HONG Hanxin, WANG Longhao, LIU Huihui, PENG Hu, WU Hao, YANG Tao

2023, 43 (3): 261-268.
doi: 10.3969/j.issn.1674-8115.2023.03.001

Abstract ( 191 )

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Objective ·To explore the hearing phenotype of Timm8a^-^/- mice and the function of translocase of inner mitochondrial membrane 8A(Timm8a)gene in inner ear by constructing Timm8a gene knockout mice. Methods ·Timm8a^-^/- mice were designed and constructed. PCR and Western blotting were used to verify whether the construction was successful. The body size and weight of Timm8a^-/- mice and wild type (WT) mice aged one-month were observed and compared. Immunofluorescence staining was used to observe the expression and distribution of TIMM8A protein in the cochlea of WT mice. Auditory brainstem response (ABR) was used to compare the hearing threshold of Timm8a^-^/- mice and WT mice. Toluidine blue staining was performed to observe the morphology of organ of Corti (OC), spiral ganglion neuron (SGN) and stria vascularis (SV) in the inner ear of the two kinds of mice. Transmission electron microscope was used to observe the ultrastructure of mitochondria in inner ear hair cells (HCs), SGN cells and SV cells of the two kinds of mice, and the proportion of abnormal mitochondria was counted. Results ·The results of PCR showed that Timm8a gene had been successfully knocked out, and the results of Western blotting showed that there was no TIMM8A proteins in the cochlea, brain, heart and skeletal muscle tissues. The both results indicated that Timm8a^-^/- mice were successfully constructed. The results of immunofluorescence staining showed that TIMM8A was abundantly expressed in the cochlea of WT mice, and was highly expressed in the OC, SGN and SV. Compared with WT mice, Timm8a^-^/- miceaged one-month developed slower, had lighter body weight and significantly higher hearing threshold (all P<0.05), their amplitude of Ⅰ wave of ABR was decreased and the latency was prolonged. The results of toluidine blue staining showed that compared with WT mice, there was no significant change in the shape and number of SGN cells in the inner ear, but the thickness of SV in the middle turn and basal turn of the cochlea was reduced (both P<0.05). The results of transmission electron microscope showed that compared with WT mice, the structure of mitochondria in inner ear HCs, SGN cells and SV cells of Timm8a^-^/- mice was abnormal, and the proportion of abnormal mitochondria was significantly increased (all P<0.05). Conclusion ·Timm8a^-^/- mice are successfully constructed in this study, and the elevated hearing threshold of Timm8a^-^/- mice may be related to the abnormal ultrastructure of mitochondria in inner ear.

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Effect of high hydrophilic electrospun short fibrous sponge on wound repair

FU Xiaohan, WANG Juan, CUI Wenguo, WANG Yan

2023, 43 (3): 269-277.
doi: 10.3969/j.issn.1674-8115.2023.03.002

Abstract ( 192 )

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Objective ·To construct an electrospun short fibrous sponge (Sponge@GO) laden with graphene oxide (GO) for chronic wound healing. Methods ·Two types of short fibrous sponges (Sponge and Sponge@GO) without and with GO were prepared by means of electrospinning, homogenizing, shaping and crosslinking with glutaraldehyde, respectively. The internal structures of the two sponges were observed with a scanning electron microscope (SEM), and their hydrophilic properties were observed via contact angle and water absorption rate. The biocompatibility of the sponge was verified by CCK-8 and live/dead staining. Twelve 6-week-old SD male rats were divided into control group, Sponge group and Sponge@GO group, with 4 rats in each group. The diabetes models were established by intraperitoneal injection of 1% streptozotocin solution, and three full-layer skin defects with a diameter of 1.0 cm were prepared on the back of each rat after modelling. Covering on the wound, the material was fixed with medical gauze. The control group was only covered with sterile gauze dressing. The wound healing rate was measured and calculated on Day 7 and 14, respectively, while hematoxylin-eosin (H-E) staining and Masson staining were performed on tissues within 0.5 cm around the wound to observe pathological changes. The angiogenesis was observed by α-smooth muscle actin (α-SMA) immunofluorescence staining on Day 14. Results ·SEM observation showed that the fiber diameter of Sponge@GO was significantly thinner and the porosity increased. The two types of short fiber scaffolds basically reached the maximum water uptake within 10 min, but the Sponge@GO scaffold showed better water absorption performance. The water contact angle of Sponge@GO scaffold was significantly smaller than that of Sponge, and the difference was statistically significant (P=0.000). The results of CCK-8 method showed that on Day 3 and 5, the Sponge group had better cell proliferation compared with the control group (both P<0.05), while there was no statistical significance between Sponge@GO group and control group. The results of live/dead staining showed that all the three groups of cells showed good cell growth trend. SEM and fluorescence staining showed that there were more cells in the Sponge@GO scaffold. In vivo experiment, no infection was found on the wound surface of the three groups of rats. The wound healing rate of Sponge@GO and Sponge groups was significantly higher than that of control group on Day 7 (both P<0.05). On Day 14, the wound healing rate of the Sponge@GO group was still significantly higher than that of the control group (P=0.009), while the difference between the Sponge group and the control group was not statistically significant. On Day 14, H-E staining showed more mature granulation tissue and more uniform and dense structure in the Sponge@GO group; Masson staining showed more dense collagen and significant epithelialization in the Sponge@GO group; α-SMA immunofluorescence staining showed more neovascularization and higher density in the Sponge@GO group. Conclusion ·Sponge@GO sponge can ensure micro-moist environment on the wound surface after absorbing exudate and has shown promising results in promoting wound healing.

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Expression of sorting nexin 1 in pancreatic ductal adenocarcinoma and its mechanism in promoting PDAC progress

PAN Hong, LIAO Yingna, GAI Yanzhi, QIAN Liheng, NIE Huizhen

2023, 43 (3): 278-292.
doi: 10.3969/j.issn.1674-8115.2023.03.003

Abstract ( 159 )

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Objective Methods ·The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database and the GSE15471 dataset in Gene Expression Omnibus (GEO) database were used to analyze the SNX1 mRNA expression in PDAC and normal pancreas tissues. Immunohistochemistry staining (IHC) was used to detect the SNX1 expression in PDAC and para-carcinoma tissues. The mRNA and protein levels of SNX1 in hTERT-HPNE cells and PDAC cells were detected by quantitative real-time PCR (qPCR) and Western blotting. CCK8 method, plate clonal formation experiment, cell scratch assays and flow cytometry (FCM) were used to detect changes of the proliferation, migration and apoptosis levels in AsPC-1 and Capan-1 cells caused by transfection siRNAs. Capan-1 cell line with stable knockdown of SNX1 was constructed, and the subcutaneous tumorigenesis experiment in nude mice was performed to detect the effect of SNX1 knockdown on the proliferation capacity of cells in nude mice. Immunofluorescence (IF) was used to determine the distribution of SNX1 in PDAC cells, and TMR-dextran was used to detect the changes of macropinocytosis levels of AsPC-1 and Capan-1 cells induced bytransfection siRNAs. Gene Set Enrichment Analysis (GSEA) was performed to predict SNX1 related signaling pathways. The transforming growth factor-β (TGF-β) signaling pathway was selected for subsequent analysis and experimental verification. Capan-1 and AsPC-1 cell lines with stable overexpression of SNX1 were constructed and treated with TGF-β signaling pathway inhibitor Oxymatrine (Oxy). CCK8 method, plate clonal formation experiment, cell scratch assays, FCM and TMR-dextran were used to detect the effects of Oxy treatment on the changes of the proliferation, migration, apoptosis and macropinocytosis levels of the cells caused by SNX1 overexpression. Results ·The results of combined analysis of TCGA and GTEx databases showed that the expression of SNX1 mRNA in PDAC tissues was higher than that in normal pancreas tissues, and the results of GSE15471 dataset analysis showed that the expression of SNX1 mRNA in PDAC tissues was higher than that in para-carcinoma tissues (both P=0.000). IHC results showed that the expression of SNX1 in cancer tissues of PDAC patients was also higher than that in para-carcinoma tissues. qPCR and Western blotting results showed that compared with hTERT-HPNE cells, the mRNA and protein levels of SNX1 in PDAC cells were up-regulated (all P<0.05). SNX1 knockdown could inhibit the proliferation and migration capacity of PDAC cells, down-regulate the macropinocytosis levels of PDAC cells, and promote their apoptosis. On the contrary, SNX1 overexpression led to opposite phenotype. Meanwhile, SNX1 knockdown could inhibit the proliferation capacity of Capan-1 cells in nude mice. IF results showed that SNX1 was colocalized with lysosomes in PDAC cells. GSEA analysis demonstrated that SNX1 expression was correlated with apoptosis, tricarboxylic acid cycle, TGF-β and phosphoinositide 3-kinase-serine/threonine-protein kinase-mammalian target of rapamycin signaling pathway. SNX1 knockdown in PDAC cells could inhibit the activation of TGF-β signaling pathway, SNX1 overexpression could promote this pathway, and TGF-β signaling pathway inhibitor Oxy could inhibit the phenotypic changes caused by SNX1 overexpression. Conclusion SNX1 is highly expressed in PDAC cells and tissues. SNX1 promotes the proliferation, migration capacity and macropinocytosis levels, and inhibits cell apoptosis by activating the TGF-β signaling pathway in PDAC cells. · ·To explore the expression changes of sorting nexin 1 (SNX1) in the occurrence and development of pancreatic ductal adenocarcinoma (PDAC) and its effect on the proliferation, migration, apoptosis and micropinocytosis of PDAC cells, and analyze its molecular mechanism to promote the progression of PDAC.

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Expression of tetraspanin 1 in breast cancer and its mechanism in promoting the progression of breast cancer

CAO Yuan, WANG Hongxia, ZHU Ying, LI Junjian

2023, 43 (3): 293-300.
doi: 10.3969/j.issn.1674-8115.2023.03.004

Abstract ( 170 )

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Objective ·To investigate the expression of tetraspanin 1 (TSPAN1) in breast cancer and its effect on the migration and invasion of breast cancer cells. Methods ·Immunohistochemistry staining (IHC) was used to detect the expression of TSPAN1 in breast cancer tissues and para-tumor tissues from 106 clinical patients, and to analyze its correlation with the clinical characteristics of patients. The Cancer Genome Atlas (TCGA) database was used to analyze the expression of TSPAN1 mRNA in breast cancer tissues and para-tumor tissues, and its correlation with the clinical characteristics of patients. After down-regulation of TSPAN1 in breast cancer cells MDA-MB-231 and SUM159PT, the effects of TSPAN1 on migration and invasion of cells were detected by wound healing assay and transwell assay, and the expression of epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and vimentin) were detected by Western blotting. Results ·IHC results showed that the expression of TSPAN1 in breast cancer tissues was higher than that in para-tumor tissues (P=0.000), and the expression of TSPAN1 in total TNM stages, M stages, N stages and pathological grades of breast cancer tissues showed statistically significant differences (all P<0.05). The results of transcriptome sequencing data from TCGA database showed that the expression of TSPAN1 mRNA in breast cancer tissues was higher than that in para-tumor tissues (P=0.000), and its expression in TNM Ⅲ?Ⅳ stages was higher than that in TNMⅠ?Ⅱ stages (P=0.007). After down-regulation of TSPAN1, the migration and invasion ability of MDA-MB-231 and SUM159PT cells were decreased, the expression of E-cadherin was increased and the expressions of N-cadherin and vimentin were decreased (all P<0.05). Conclusion ·TSPAN1 is highly expressed in breast cancer tissues, which can promote the migration and invasion of breast cancer cells.

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Clinical analysis of rituximab for adult refractory primary membranous nephropathy

FENG Linhong, WANG Yakun, WU Qianqian, ZHU Yingchun, BAI Shoujun

2023, 43 (3): 301-307.
doi: 10.3969/j.issn.1674-8115.2023.03.005

Abstract ( 322 )

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Objective ·To evaluate clinical efficacy and safety of rituximab (RTX) in the patients with refractory primary membranous nephropathy (PMN). Methods ·A retrospective analysis was carried out on the patients with refractory PMN, who had recurred or had not achieved clinical remission after more than 1 year of treatment with glucocorticoid and cyclosporine, cyclophosphamide or tacrolimus, admitted to the Department of Nephrology, Qingpu Branch of Zhongshan Hospital, Fudan University from July 2018 to April 2022. They received 2 doses of RTX. The single dose of RTX was 1 000 mg, and the interval between the two doses was 2 weeks. After 6 months, the numbers of peripheral blood B cells of the patients were detected. If the count of peripheral blood B cells were greater than 5 cell/μL, another 1 000 mg RTX would be added. The main indicators were serum albumin, serum creatinine, urinary protein/creatinine ratio (UPCR), blood antibody against phospholipase A2 receptor (PLA2R) antibody, peripheral blood B cell count, and serum total IgG level. The clinical efficacy and safety of the treatment regimen were evaluated by observing the change of the main indicators of patients and adverse reactions. Results ·A total of 18 patients were included, with an average age of (58.17±16.73) years, including 11 males. The total dose of RTX was (2 222.22±485.07) mg, and the follow-up time after RTX treatment was (14.9±4.9) months. At the last follow-up, the serum albumin level was significantly higher than that before RTX treatment [(36.50±5.33) g/L vs (27.61±8.59) g/L, P=0.009]; the serum creatinine level was stable (P>0.05); the value of UPCR decreased significantly [863.30 (203.20, 2 291.75) mg/g vs 2 954.00 (1 458.00, 7 260.75) mg/g, P=0.047]; the PLA2R antibody decreased significantly [(44.32±33.71) RU/mL vs (168.40±88.40) RU/mL, P=0.015]; the peripheral blood B cell count decreased significantly [(37.89±12.43) cell/μL vs (246.40±239.98) cell/μL, P=0.009]; the total blood IgG level was stable (P>0.05). After RTX treatment, 8 patients achieved complete remission (44.4%), 7 patients achieved partial remission (38.9%), and the overall effective rate was 83.3%; only 3 patients were unrelieved (16.7%). In terms of adverse reactions, 1 patient had transfusion allergy reaction, and 1 patient had pulmonary infection. Conclusion ·For the patients with refractory PMN who have relapse or do not relieve after traditional immunosuppressive therapy, RTX treatment can effectively induce clinically complete remission or partial remission with good safety.

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Effect of postpartum pelvic floor muscle training on improving pelvic floor function

RAO Lin, ZHANG Linna, YUAN Jiaqi, LU Bangchun

2023, 43 (3): 308-313.
doi: 10.3969/j.issn.1674-8115.2023.03.006

Abstract ( 233 )

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Objective ·To evaluate the effect of pelvic floor muscle training (Kegel training) on the rehabilitation of pelvic floor function within 1 year after delivery. Methods ·From January to April 2020, primiparas with different degrees of urinary incontinence or pelvic organ prolapse were selected and divided into exercise group (147 cases) and control group (194 cases). The exercise group received Kegel training at 6 weeks of the postpartum period, while the control group received general postpartum health education only. At 6 weeks and 1 year after delivery, these postpartum women in the two groups were investigated with the general information questionnaire and International Consultation Incontinence Questionnaire-UI Short Form (ICIQ-SF). The pelvic floor muscle strength was measured (the pelvic floor muscle strength grade>Ⅲ indicates normal muscle strength). The pelvic organ prolapsed quantitation (POP-Q) score was assigned accordingly. The urinary incontinence score, pelvic floor muscle strength and pelvic floor organ prolapse were compared between the two groups, and the effect of pelvic floor muscle training was evaluated. Results ·In the exercise group, 20 postpartum women lost contact during follow up sections, and 28 women in the control group were unable to be contacted within 1 year. In the exercise group, the proportion of women with normal pelvic floor muscle strength at 1 year postpartum was significantly higher than that at 6 weeks postpartum (56.0% vs 34.7%, P=0.000), and the incidence of incontinence at 1 year postpartum was significantly lower than that at 6 weeks postpartum (25.2% vs 36.7%, P=0.040). In the control group, the proportion of women with normal pelvic floor muscle strength at 1 year postpartum was significantly higher than that at 6 weeks postpartum (43.4% vs 32.5%, P=0.033), and the incidence of incontinence at 1 year postpartum was significantly lower than that at 6 weeks postpartum (17.5% vs 28.9%, P=0.011). At 1 year postpartum, the proportion of women with normal pelvic floor muscle strength in the exercise group was higher than that in the control group (56.0% vs 43.4%, P=0.033). The improvement rate of muscle strength in the exercise group was higher than that in control group (50.4% vs 35.5%, P=0.011). There was no significant difference in the improvement rate of pelvic organ prolapse and frequency of urinary incontinence between the exercise group and the control group (P>0.05). Conclusion ·Postpartum pelvic floor muscle training can improve pelvic floor muscle strength, but has no significant effect on improving pelvic floor dysfunction in the current samples. The urinary incontinence condition and pelvic floor muscle strength of women improve 1 year after delivery, indicating that there is a mechanism for self recovery of pelvic floor muscle, but it may take a long time.

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Effect of continuous positive urine ketone body on clinical outcomes of pregnant women with gestational diabetes mellitus and newborn

ZHANG Yue, QU Lei, GU Qin, ZHU Yiqing, MA Liying, SUN Wenguang

2023, 43 (3): 314-319.
doi: 10.3969/j.issn.1674-8115.2023.03.007

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Objective ·To explore the effect of continuous positive urine ketone body in pregnant women with gestational diabetes mellitus (GDM) on the maternal and infant outcomes. Methods ·A total of 168 GDM pregnant women who attended the Nutrition Clinic of the International Peace Maternal & Child Health Hospital, Shanghai Jiao Tong University School of Medicine from January 2021 to January 2022 and gave birth in the hospital were selected as the study subjects. According to the difference of urine ketone body test results in prenatal examination, they were divided into ketone body-positive group (56 cases, the pregnant women had ketone body test positive for three times or more after the diagnosis of GDM) and ketone body-negative group (112 cases, the ketone body test was continuously negative after the diagnosis of GDM). The general information included clinical data and laboratory indicators of pregnant women and clinical outcomes of pregnant women and their newborns were collected and compared. Results ·There were no statistically significant differences in clinical data and laboratory indicators of pregnant women between the two groups, among which the body mass index before pregnancy, weight change before diagnosis of GDM, family history of diabetes mellitus, history of GDM, total cholesterol and triacylglycerol levels in the early pregnancy, fasting blood glucose and insulin levels in the middle pregnancy had no significant correlation with the production of urine ketone body. The results of clinical outcome indicators of pregnant women showed that there were statistically significant differences in weight change (P=0.000; RR=6.000, 95% CI 1.251?28.777) and rate of weight gain (P=0.000; RR=1.829, 95% CI 1.132?2.953) after diagnosis of GDM between the two groups. The results of neonatal clinical outcome indicators showed that there was statistically significant difference in the neonatal hospitalization rate (P=0.023; RR=2.167, 95% CI 1.059?4.434) between the two groups; among them, there were 4 adverse events in the ketone body positive group and no such adverse events in the ketone body negative group. Conclusion ·The continuous positive urine ketone body of pregnant women with GDM may increase the risk of insufficient weight gain in pregnant women and neonatal hospitalization. It is recommended to timely detect and intervene in clinical practice.

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Efficacy of radiotherapy in patients with rectal cancer undergoing chemotherapy and surgery: a retrospective study based on the SEER database

WANG Anjun, LIU Ningning

2023, 43 (3): 320-332.
doi: 10.3969/j.issn.1674-8115.2023.03.008

Abstract ( 147 )

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Objective ·To evaluate the survival effects of neoadjuvant radiation therapy and adjuvant radiotherapy on the patients with rectal cancer treated with chemotherapy and surgery by using the Surveillance, Epidemiology and End Results (SEER) database of the United States. Methods ·The patients with pathologically confirmed rectal cancer and treated with chemotherapy and surgical resection from 2005 to 2015 in the SEER database were included; the patients with autopsy or death-only proof of rectal cancer, or without follow-up time and incomplete clinical data were excluded. All the patients were divided into neoadjuvant radiotherapy combined with surgery group (RT+S group), surgical treatment group (S group) and surgery combined with adjuvant radiotherapy group (S+RT group). The propensity score matching (PSM) was used to match the included subjects in each group at the 1∶1 ratio, and the restricted mean survival time (RMST) was used to estimate the mean survival of rectal cancer patients over 5 and 10 years. Cox proportional risk models were used to determine the effects of neoadjuvant and adjuvant radiotherapies on overall survival (OS) and tumor-specific survival (CSS) in the patients with rectal cancer, and the specific benefit groups of neoadjuvant and adjuvant radiotherapies were determined by stratified analysis of patients. Results ·From 2005 to 2015, 8 975 patients with rectal cancer who received chemotherapy and surgery were included, including 1 079 in the S group, 5 991 in the RT+S group, and 1 905 in the S+RT group. After PSM, the clinical base characteristics of the groups were balanced and comparable. The patients in the RT+S group had a significantly improved prognosis in 5 and 10 years compared with the S group (all P=0.000) after PSM, while the patients in the S+RT group had a significantly improved prognosis in 5 years only (both P<0.05) and no significant improvement in 10 years (both P>0.05). Multivariate Cox regression analysis showed that neoadjuvant radiotherapy was an independent protective factor for the patients′ OS and CSS (both P=0.000), while adjuvant radiotherapy was not (both P>0.05). Subgroup analysis showed that neoadjuvant radiotherapy had no significant protective effect on OS and CSS in the patients aged<50 years, with highly differentiated tumors, tumor size≤30 mm or TNM stage Ⅰ?Ⅲ (all P>0.05); whereas adjuvant radiotherapy had significant protective effects on OS and CSS in the patients with poorly differentiated/undifferentiated tumors, tumor size>50 mm or TNM stage Ⅳ (all P<0.05). Conclusion ·For the patients with rectal cancer treated with chemotherapy and surgery, neoadjuvant radiotherapy has a significant survival benefit, but it may not be applicable for the patients aged<50 years, with highly differentiated tumors, tumor size≤30 mm, or TNM stage Ⅰ?Ⅲ; whereas the patients with poorly differentiated/undifferentiated tumors, tumor size>50 mm, or TNM stage Ⅳ may benefit from adjuvant radiotherapy.

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Interventions to enhance return-to-work among young and middle-aged cancer survivors: a systematic review

ZHANG Yuanyuan, WU Anqi, WU Jie, ZHU Yaqi, LI Mengyao, YAN Dexiu, ZHANG Yaqing, HOU Lili

2023, 43 (3): 333-341.
doi: 10.3969/j.issn.1674-8115.2023.03.009

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Objective ·To systematically evaluate the application of return-to-work intervention programs to young and middle-aged cancer survivors and its effectiveness in improving work-related outcomes in cancer survivors. Methods ·An initial literature search of eight electronic databases, including PubMed, Cochrane Library, Embase, CNKI and Wanfang was conducted with a time frame from inception to Aug 2nd, 2022 to collect randomized controlled trials (RCTs) and quasi-experimental studies of return-to-work interventions on work-related outcomes among cancer survivors. Two researchers independently conducted literature screening, data extraction, and methodological quality evaluation using the JBI (Joanna Briggs Institute) Methodology Quality Evaluation Tool. Results ·A total of 13 original studies were included, involving 11 return-to-work intervention programs, containing 2 045 cancer survivors. The results of the systematic evaluation showed that 10 of the intervention programs were multidisciplinary, with intervention modules on disease/mental health education, group discussions, physical rehabilitation, work capacity exercises, multidisciplinary team meetings and counselling. Among them, three interventions also included employers in the support program. The duration of the interventions ranged from 7 d to one year. Eight of the included interventions took return-to-work rates as a primary outcome, but only three reported that the difference was statistically significant, two of which were quasi-experimental studies without control group. Besides, no clear positive effects were found on work-related outcome such as length of return-to-work, change of work status, work ability, and work meaning. Conclusion ·The content, format, intensity and frequency of return-to-work intervention programs for cancer survivors vary widely, and the effects of interventions on work-related outcomes are still unclear. Researchers should further explore the mechanisms that influence cancer survivors′ return-to-work, and develop multidisciplinary intervention programs based on this to effectively help young and middle-aged cancer survivors return-to-work and society. In addition, due to the limitations of study quality and intervention program heterogeneity, more high-quality experimental studies are needed to further validate the above findings.

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Application of digital terrain analysis to the study of cerebral cortex morphology

YANG Zihao, CHEN Nan, LIN Siwei

2023, 43 (3): 342-349.
doi: 10.3969/j.issn.1674-8115.2023.03.010

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Objective ·To propose a theoretical method based on geosciences for the expression and quantitative description of the surface morphology of the cerebral cortex. Methods ·Eighty-five samples of normal cognition (NC) and 84 samples of Alzheimer′s disease (AD) were downloaded from the Alzheimer′s Disease Neuroimaging Initiative (ADNI) database, and the cerebral cortex data of magnetic resonance imaging (MRI) images of the human brain were extracted by using SPM 12 software package. The undulating cerebral cortex image was mapped into the point cloud data after three-dimensional reconstruction, and the digital elevation model (DEM) of the brain was further constructed according to the theoretical method of digital terrain analysis to realize the digital expression of the cerebral cortex morphology. The study introduced terrain factors′ indicators such as roughness, relief amplitude and elevation in geoscience to quantitatively describe the morphological characteristics of the cerebral cortex. Covariance analysis was conducted with age as the covariate, and independent sample t test was conducted with gender into groups and NC samples and AD samples as the variables, terrain factors as the group and left and right hemispheres as the variables to reveal the change rule of cerebral cortex morphology. Results ·The roughness, relief amplitude and thickness of the cerebral cortex were linearly distributed with age, and the differences between the AD group and the NC group were all statistically significant (all P<0.05); the roughness and relief amplitude of both men and women showed that the AD group was larger than the NC group (both P<0.05), the cortical thickness showed that the AD group was smaller than the NC group (P=0.000), and the elevation only had an inter-group difference in women (P=0.043); the left hemisphere roughness, relief amplitude and elevation values of NC group were higher than those of the right hemisphere (all P<0.05), while AD only had inter-group differences in elevation indicators (P=0.000). Conclusion ·Terrain factors can significantly distinguish the cerebral cortex differences between AD and NC patients, and has a good distinction when age, gender and left and right hemisphere are used as variables. It is expected to provide an auxiliary means for the medical quantification of cerebral cortex morphology.

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Clinical and genetic characteristics of Charcot-Marie-Tooth disease with cerebellar ataxia

ZHU Xiaowei, ZHONG Ping, CAO Li, LUAN Xinghua

2023, 43 (3): 350-357.
doi: 10.3969/j.issn.1674-8115.2023.03.011

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Charcot-Marie-Tooth disease (CMT) is a group of hereditary motor and sensory neuropathy predominantly with peripheral neuropathy. It is characterized by progressive symmetric distal-predominant weakness, amyotrophy, sensory loss and reduced or absent deep tendon reflexes. CMT is usually divided into CMT1 type with demyelination and CMT2 type with axonal lesions according to electrophysiological and pathological characteristics. In addition to peripheral nervous system lesions, some CMT subtypes may also involve the central nervous system or other organs. The CMT patients with cerebellar system involvement also have cerebellar ataxia which can be seen as CMT1F type and CMT2E type caused by mutations in neurofilament light chain(NEFL) gene, CMT2Z with mutations in MORC family CW-type zinc finger 2 (MORC2) gene, CMT-6B with mutations in solute carrier family 25 member 46 (SLC25A46) gene, CMT2B2 with mutations in polynucleotide kinase 3′-phosphatase (PNKP) gene and so on. In recent years, CMT overlapping phenotypes have become a hot topic of research, among which CMT with cerebellar ataxia is a clinically and genetically heterogeneous group of disorders, and is prone to misdiagnosis clinically. This article reviews the clinical and genetic characteristics of CMT with cerebellar ataxia, aiming to provide reference for the earlier recognition and therapeutic strategies.

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Physiological function of nerve injury-induced protein 1 and its role in relevant diseases

WU Zhaoyu, XU Zhijue, PU Hongji, WANG Xin, LU Xinwu

2023, 43 (3): 358-364.
doi: 10.3969/j.issn.1674-8115.2023.03.012

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Nerve injury-induced protein 1 (NINJ1) is a cell-surface adhesion molecule containing an extracellular adhesion domain and two transmembrane domains. NINJ1 is named for its original discovery in damaged nerve endings. It is expressed in a variety of tissues and cells, with high expression in epithelial and myeloid cells. NINJ1 regulates nerve regeneration by promoting Schwann cell precursors and pluripotent pericytes to differentiate into Schwann cells. In diabetes-induced peripheral nerve and vascular damage, NINJ1 not only promotes nerve repair, but also regulates penile angiogenesis via angiopoietin 1 (ANG1)/tyrosine-protein kinase receptor tie-2 (TIE2) signaling pathway. NINJ1 also participates in the maturation of vitreous vascular network, which is associated with changes in the proportion of ANG1 and ANG2 in pericytes. NINJ1 mediates inflammatory cell migration across the endothelium through its extracellular adhesion domain, and thus aggravates central nervous system inflammation. However, NINJ1 cleaved by matrix metalloproteinase 9 (MMP9) can inhibit macrophage inflammatory activation, and its mimic peptide is expected to treat atherosclerosis. In addition to regulating the inflammatory phenotypes of myeloid cells, NINJ1 actively mediates plasma membrane rupture and regulates programmed cell death, which is involved in host defense against exogenous infection. Moreover, NINJ1 is up-regulated in a variety of tumor tissues, and regulates tumor suppressor P53 activity via the P53-NINJ1 loop, which mediates tumor growth and metastasis. The current review summarizes the physiological function of NINJ1 and its key regulatory roles in pathological processes, and discusses its potential value in immunomodulation and tissue regeneration, in order to provide new ideas for the prevention and treatment of injury, inflammation and tumor-related diseases.

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Research progress in ferroptosis regulation in the treatment of liver diseases

CHEN Chen, CHENG Zhuoan, WANG Cun, XIA Qiang

2023, 43 (3): 365-373.
doi: 10.3969/j.issn.1674-8115.2023.03.013

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Ferroptosis is a form of cell death that results from accumulation of lipid reactive oxygen species, marked by iron-dependent oxidative damage of phospholipids. Accumulation of iron and lipid hydroperoxides are hallmarks of ferroptosis. Diverse biological contexts, including iron handling, redox homeostasis, imbalance of lipid synthesis, participate in ferroptosis. Mechanistically, pathways of ferroptosis regulation involving System X_c^--glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, coenzyme Q10 (CoQ10)-ferroptosis suppressor protein 1 (FSP1)-ubiquinol axis, GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4)-dihydrofolate reductase (DHFR) axis, dehydrogenase (DHODH)-ubiquinol axis have been discovered. Ferroptosis has been implicated in multiple liver diseases, such as hepatocellular carcinoma, liver ischemia-reperfusion injury, steatohepatitis, liver fibrosis, cirrhosis and liver metabolic diseases. Elucidating its mechanism offers various tractable nodes for therapeutic intervention. Here, we summarize insights into the molecular characteristics, biological processes, regulatory pathways of ferroptosis and its recent advances in the treatment of liver diseases.

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Research progress in the role and mechanism of lactylation in diseases

GE Lingling, HUANG Hongjun, LUO Yan

2023, 43 (3): 374-379.
doi: 10.3969/j.issn.1674-8115.2023.03.014

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Lactic acid is a product of cell respiration. After entering into cells, glucose is metabolized to pyruvate by glycolysis. When the oxygen supply is sufficient, pyruvate is converted to acetyl coenzyme A through pyruvate dehydrogenase in the mitochondrial matrix to participate in the tricarboxylic acid cycle and provide necessary energy for cells. Pyruvate is catalysed by lactate dehydrogenase in the cytoplasm to produce lactate while cells are grown under hypoxic conditions. Lactate not only provides energy for mitochondrial respiration, but also plays important roles in inflammatory responser, wound repair, memory formation and neuroprotection as well as tumor growth and metastasis and other pathophysiological processes through autocrine, paracrine, and endocrine forms, which affects the development and prognosis of diseases. Epigenetic modification regulates gene replication, transcription and translation by covalently adding or hydrolyzing functional groups on histones and DNA through related enzymes and affects the biological effects of cells. Histones are the major structural proteins of eukaryotic chromosomes. Their post-translational modifications, such as methylation and acetylation, affect their affinity with DNA, change chromatin structures, and are widely involved in regulation of gene expression. Recent studies have found that histones can undergo lactylation, which is a new epigenetic modification by adding lactate to lysine residues on histones. As the research deepens, numerous evidences reveal that lactylation also occurs on non-histone proteins. The discovery of lactylation has expanded our understanding of lactate functions in the pathogenesis of diseases. In this review, we summarize the roles and mechanisms of lactylation in tumor, inflammatory and neural system diseases, in order to provide new ideas for the research, diagnosis and treatment of these diseases.

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Application and research progress of tetrahedral framework nucleic acids in the field of medicine

XIE Shasha, LÜ Yehui, LIN Jian

2023, 43 (3): 380-384.
doi: 10.3969/j.issn.1674-8115.2023.03.015

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Since the first proposal by Seeman in 1982, DNA nanostructures have been gradually improved, and have been widely developed and applied to the field of biomedical fields. In recent years, as a representative of 3D DNA nanostructures, tetrahedral framework nucleic acids (tFNA) has made certain research progress and has good application prospects in frontier fields such as biosensors, tumor therapy, antigen detection, regenerative medicine, with the advantages of their good biocompatibility, editability, high stability and easy preparation. This paper briefly describes the concepts of tFNA, and summarizes the applications and research progress of tFNA in the following fields from the perspective of therapeutic applications: ① Building novel self-assembled complexes to improve the efficacy of free drugs, carrying small RNA molecules to slow down tumor progression, and self-assembled complexes for targeted therapy, etc, as biological vectors and tumor drug delivery. ② Regulating inflammation and immune response, such as reducing the level of inflammatory factors, treating inflammatory diseases, preventing diabetes, and acting as immunomodulators, etc. ③ Enhancing tissue regeneration, such as promoting stem cell proliferation and differentiation, stimulating peripheral nerve regeneration, and facilitating wound repair through angiogenesis. This review summarizes the research progress of tFNA, and looks forward to its application prospects based on the analysis of the shortcomings of existing research, in order to provide reference for further research.

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Application of non-invasive methods of radiology to the osteoporosis

LIU Chenjun, YIN Bohao, SUN Hui, ZHANG Wei

2023, 43 (3): 385-390.
doi: 10.3969/j.issn.1674-8115.2023.03.016

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Early screening and timely treatment can effectively reduce the morbidity and mortality of the osteoporotic fractures, and hence efficient and accurate non-invasive radiological method is crucial. Non-invasive imaging methods of radiology frequently encounter less resistance in the promotion of therapeutic activities than invasive procedures like bone biopsy and perfusion imaging. Although dual-energy X-ray absorption has been established as the primary diagnostic method for osteoporosis, its efficacy is relatively constrained due to various parameters, and it is challenging to accurately depict the true status of bone structure. In recent years, radiological techniques have developed rapidly. Computed tomography, magnetic resonance imaging, quantitative ultrasound and other imaging techniques have been widely used in the diagnosis of osteoporosis in the research and clinical practices, which provides more comprehensive and detailed information about bone mineral density and bone structure for early diagnosis, treatment design and prognosis monitoring. As clinic and computer science crosstalk closely, it will become possible for artificial intelligence to assist or even independently perform imaging analysis and disease screening in image data base. This article reviews the individual characteristics and latest research progress of the non-invasive radiological techniques for the osteoporosis.

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Experience of laparoscopic ultrasound-guided ablation of diaphragmatic liver tumors

ZHANG Yin, WU Xian, XIE Bingluan, WANG Yi

2023, 43 (3): 391-396.
doi: 10.3969/j.issn.1674-8115.2023.03.017

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Objective ·To investigate the safety and effectiveness of laparoscopic ultrasound-guided microwave ablation for phrenic surface liver tumors, as well as the specific experience of its use. Methods ·A retrospective analysis was performed on 13 cases of diaphragmatic liver tumor who received laparoscopic ultrasound-guided microwave ablation in Zhejiang University of Traditional Chinese Medicine Affiliated Wenzhou Hospital from November 2019 to April 2021. The falciform ligament, coronal ligament and deltoid ligament were severed according to the need, and gauze pads were filled on the diaphragmatic surface or visceral of the liver. Laparoscopic ultrasound scan of the liver was performed to determine the location of the tumor and whether there were new tumors. Meanwhile, ultrasound contrast agent was used to perform multi-point and multi-angle ablation of the tumor after biopsy. During the process of needle withdrawal, laparoscopic direct observation was performed to observe whether there was bleeding, and needle path ablation was performed. After ablation, contrast-enhanced ultrasound was repeated and additional ablation was performed if necessary. Perioperative complications were observed and preoperative and postoperative blood biochemical indexes, white blood cells level and postoperative MRI manifestations were compared. Results ·All the 13 patients were successfully treated with laparoscopic ultrasound-guided microwave ablation. There were no serious complications such as diaphragm injury, arrhythmia, pneumonia, pneumothorax, massive bleeding, biliary fistula and intestinal injury. The white blood cells before surgery [(4.9±1.0)×10⁹/L] and day 2 after surgery [(8.7±2.5)×10⁹/L] were significantly different (P=0.000). The glutamic-pyruvic transaminase [15.0 (22.0, 77.5) U/L] before surgery and day 2 after surgery [69.0 (135.0, 371.0) U/L] were significantly different (P=0.013). One month after the operation, MRI enhancement confirmed that the total necrosis rate of the lesion was 100%. Conclusion ·Laparoscopic ultrasound-guided hepatic tumor ablation, which is first performed under laparoscopy, forms a safe isolation zone around the liver through the establishment of pneumoperitoneum, severed ligament, gauze isolation and other methods. Then, under the direct vision of laparoscopic ultrasound probe, the diaphragmatic liver tumors are ablated to achieve a safer and more effective method.

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