Journal of Shandong University (Health Sciences)

Effects of programmed necrosis and ferroptosis regulated by toll-like receptor 4 on acetaminophen-induced liver injury

SHEN Haitao, QIAO Yaqin, DONG Ping, LU Yan

Journal of Shandong University (Health Sciences). 2024, 62(4): 1-8. doi:10.6040/j.issn.1671-7554.0.2023.1016

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Objective To explore whether toll-like receptor 4(TLR4)further affects the process of acetaminophen(APAP)induced liver injury and its mechanism by regulating programmed necrosis and ferroptosis. Methods Human normal hepatocytes L-02 were cultured in vitro and cell viability was detected by the CCK-8 method, and the concentrations of APAP and TAK-242 were evaluated. The experiment was divided into control group, APAP groups(1, 4, 12 h)and APAP+TAK-242 groups(1, 4, 12 h), and the TLR4 mRNA levels were compared in each group. The levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in cell homogenates of different groups were detected; The levels of nuclear factor-κB(NF-κB), interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)were detected in each group; The levels of high mobility group box 1(HMGB1), receptor interacting protein kinase 1(RIP1)and receptor interacting protein kinase 3(RIP3)were detected in each group; The intracellular Fe²⁺ content and the level of NF-κB, P53, recombinant solute carrier family 7 member 11(SLC7A11), glutathione peroxidase 4(GPX4)were detected in each group. Results The concentration of 5 mmol/L APAP and 100 nmol/L TAK-242 was determined by the CCK-8 method. Compared to the control group, the TLR4 mRNA levels of the APAP groups were positively regulated at each time point(P<0.05); Compared to the APAP groups, the levels of TLR4 mRNA in the APAP+TAK-242 groups were negatively regulated at the corresponding time points(P<0.05/3=0.016 7). Compared to the control group, the levels of ALT and AST in the APAP groups increased at each time point(P<0.05); Compared to the APAP groups, the levels of ALT and AST in the APAP+TAK-242 groups decreased at the corresponding time points(P<0.05/3=0.016 7). Compared to the control group, the mRNA expressions of NF-κB, IL-6 and TNF-α were up-regulated in the APAP groups at each time point(P<0.05); Compared to the APAP groups, the mRNA expressions of NF-κB, IL-6 and TNF-α were all down-regulated in the APAP+TAK-242 groups at the corresponding time points(P<0.05/3=0.016 7). Compared to the control group, the levels of HMGB1, RIP1, and RIP3 increased in the APAP groups at all time points(P<0.05); Compared to the APAP groups, the levels of HMGB1, RIP1, and RIP3 decreased in the APAP+TAK-242 groups at the corresponding time points(P<0.05/3=0.016 7). Compared to the control group, the content of Fe²⁺, NF-κB and P53 was increased(P<0.05), but the levels of SLC7A11 and GPX4 decreased in the APAP groups at all time points(P<0.05); Compared to the APAP groups, the content of Fe²⁺, NF-κB and P53 were decreased(P<0.05/3=0.016 7), but the levels of SLC7A11 and GPX4 increased in the APAP+TAK-242 groups at the corresponding time points(P<0.05/3=0.016 7). Conclusion Inhibition of TLR4 can negatively regulate programmed necrosis by regulating the TLR4 / HMGB1 signaling pathway and can negatively regulate the inflammatory response and ferroptosis by regulating TLR4/NF-κB signaling pathway to alleviate APAP-induced liver injury.

Animal experiment of medical thoracoscopic splanchnotomy

BAI Xiaoliang, SUN Panpan, WANG Hongli, GONG Shunzhi, SUN Yunqi, SHU Meng, QI Xiaoliang

Journal of Shandong University (Health Sciences). 2024, 62(4): 9-13. doi:10.6040/j.issn.1671-7554.0.2024.0092

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Objective To explore the feasibility of medical thoracoscopic splanchnotomy through animal experiments. Methods Four experimental pigs were given intravenous anesthesia combined with intercostal nerve block anesthesia, and preserved the spontaneous breathing state. Splanchnotomy was performed by medical thoracoscope. The operation time, blood loss, complications and technical problems were recorded. Results Medical thoracoscopic splanchnotomy was successfully performed in 4 pigs. There were no complications such as intraoperative hemorrhage, organ injury and death. Conclusion The animal experiment of medical thoracoscopic splanchnotomy is feasible, Which can provide a research basis for the clinical application of medical thoracoscopic splanchnotomy in the treatment of epigastric cancer pain.

Expression of autophagy-related protein 5 in colon cancer and its impact on the migration and invasion ability of colon cancer cells

LIU Aijing, LI Yanru, GAO Huiru, DUAN Weili, LI Peilong, LI Juan, DU Lutao, WANG Chuanxin

Journal of Shandong University (Health Sciences). 2024, 62(4): 14-23. doi:10.6040/j.issn.1671-7554.0.2024.0125

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Objective To evaluate the expression of autophagy-related protein 5(ATG5)in colon cancer and its relationship with clinicopathological features, and to analyze the effect of ATG5 on the migration and invasion ability of colon cancer cells. Methods The expression levels of ATG5 mRNA and ATG5 protein in colon cancer tissues and adjacent normal tissues were analyzed using the online analysis tool cProsite. Kaplan-Meier Plotter was used to analyze the effect of ATG5 expression level on the prognosis of colon cancer patients. The expression of ATG5 in 100 colon cancer tissues was detected by immunohistochemistry, and the correlation between the expression level of ATG5 and clinicopathological features was analyzed by χ2 and Fishers test. ATG5 was overexpressed or knocked down in colon cancer cells by transfecting plasmid or small interfering RNA(siRNA), and then the transfection efficiency and changes of microtubule-associated protein light chain 3(LC3)were detected by Western blotting. Transwell assay was used to evaluate migration and invasion ability of colon cancer cells after overexpression or knockdown. Differentially expressed genes associated with ATG5 in colon cancer were analyzed using the LinkedOmics database, and gene ontology(GO)and kyoto encyclopedia of genes and genomes(KEGG)enrichment analyses were performed. Results The expression levels of ATG5 mRNA and protein in colon cancer tissues were lower than those in adjacent normal tissues(P<0.001). The recurrence-free survival of colon cancer patients with low ATG5 expression was significantly shorter than those with high ATG5 expression(P<0.001). Immunohistochemistry showed that the expression level of ATG5 in colon cancer tissues was correlated with lymph node metastasis, and low expression of ATG5 in colon cancer patients was more likely to develop lymph node metastasis(P=0.027). Western blotting and Transwell experiments showed that after overexpression of ATG5 in SW1116 cells, the expression of LC3Ⅱ/LC3Ⅰ increased, and the migration and invasion ability of cells was weakened(P_ATG5=0.001; P_{LC3Ⅱ/LC3Ⅰ}=0.04; P_migration<0.001, P_invasion<0.001). Conversely, ATG5 knockdown in DLD1 cells led to a decrease in the expression of LC3Ⅱ/LC3Ⅰ, and an increase in the migration and invasion ability of the cells(P_ATG5#1=0.021, P_ATG5#2<0.001; P_{LC3Ⅱ/LC3Ⅰ#1}=0.013, P_{LC3Ⅱ/LC3Ⅰ#2}=0.02; P_migration<0.001, P_invasion<0.001). ATG5-related differentially expressed gene enrichment analysis suggested that ATG5 might affect colon cancer metastasis by affecting DNA damage response, chromatin organization and Notch signaling pathway. Conclusion ATG5 is lowly expressed in colon cancer and is significantly correlated with lymph node metastasis and prognosis of patients. ATG5 in colon cancer cells can increase the level of autophagy and inhibit cell migration and invasion, suggesting that ATG5 and its regulated autophagy process may become a new target for the clinical treatment of colon cancer.

Subcellular localization pattern of bromodomain containing 9 in colorectal cancer and its clinical significance

LIU Chuncheng, LIU Xiaohan, WEI Yanruoxue, LI Ziqi, LIU Yukun, ZHAO Ran

Journal of Shandong University (Health Sciences). 2024, 62(4): 24-30. doi:10.6040/j.issn.1671-7554.0.2024.0184

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Objective To investigate the protein expression level, subcellular localization pattern and clinical significance of bromodomain containing 9(BRD9)in colorectal cancer(CRC). Methods Surgical resection specimens of CRC were collected, and immunohistochemistry(EnVision method)was used to detect BRD9 protein expression and subcellular localization. The relationship between BRD9 expression and clinicopathological features and prognosis of CRC patients was analyzed. Results Among 508 CRC tissue specimens, BRD9 was overexpressed in 71.46%(363/508)of patients, and 80.31%(408/508)of patients showed nuclear positive staining in immunohistochemistry for BRD9. The expression of BRD9 was correlated with tumor size(P=0.025), lymph node metastasis(P=0.004), nerve invasion(P=0.043), differentiation grade(P=0.017)and TNM stage(P=0.002). The subcellular localization of BRD9 was correlated with lymph node metastasis(P=0.040)and TNM stage(P=0.026). The difference was statistically significant. Meanwhile, BRD9 high expression served as an independent poor prognostic factor(HR=1.994, P=0.002). More important, in patients with BRD9 low expression, cytoplasmic BRD9 expression was an independent poor prognostic factor of patients(HR=8.056, P=0.001). Conclusion The subcellular localization of BRD9 is heterogeneous in CRC patients. The high expression and cytoplasmic localization of BRD9 are related to the occurrence and development of CRC, and could be used as an independent predictor for the prognosis of CRC patients.

Value of multiple quantitative parameters of EOB-MRI in the risk assessment of progression of HHN in hepatobiliary phase

LIU Xiaowen, CAO Yongquan, HOU Mingyuan, YU Dexin

Journal of Shandong University (Health Sciences). 2024, 62(4): 31-39. doi:10.6040/j.issn.1671-7554.0.2024.0030

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Objective To explore the value of multiple quantitative parameters of gadoxetic acid(gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic(Gd-EOB-DTPA, abbreviated as EOB)enhanced MRI in predicting the risk of progression of hypovascular hypointense nodules(HHN)in hepatobiliary phase(HBP). Methods Patients with HHNs in hepatobiliary phase examined by EOB enhanced MRI(EOB-MRI)in Qilu Hospital of Shandong University were divided into stable group and unstable group through follow-up. The baseline and imaging characteristics of the lesions were observed, and some parameters were measured and calculated. The differences of baseline quantitative parameters between the two groups of HHN were compared. Receiver operating characteristic(ROC)curve was used to analyze the predictive efficiency of each quantitative parameter on nodular stability. Binary Logistic regression was used to analyze the risk factors for the progression of HHN in hepatobiliary phase. Results There were significant differences in the mean value of T₂WI signal, contrast-to-noise ratio(CNR)at T₂WI and hepatobiliary phase(CNR_T₂WI, CNR_HBP), contrast ratio at hepatobiliary phase(CR_HBP)and hepatobiliary phase enhancement rate between the two groups(P=0.045, P=0.037, P=0.043, P=0.049, P=0.003). There were significant differences in apparent diffusion coefficient(ADC)value and CR_ADC between the two groups(P<0.001, P=0.001). ROC curve analysis showed that hepatobiliary phase enhancement rate, ADC value and CR_ADC had good predictive power for evaluating HHN stability, with sensitivities of 72.2%, 96.9%, 87.5% and specificities of 72.7%, 54.5% and 63.6%, respectively. High signal intensity on diffusion-weighted imaging(DWI)and the enhancement rate of HHN in hepatobiliary phase were predictors of the progression of HHN in hepatobiliary phase. Conclusion The hepatobiliary phase enhancement rate, ADC value and CR_ADC of EOB-MRI multi-quantitative parameters are helpful for the risk stratification of HHN in hepatobiliary phase.

Correlation between frailty and body composition in elderly patients with gastric cancer

GUO Xin, MENG Jun, ZHENG Shiliang, DONG Xiuhong

Journal of Shandong University (Health Sciences). 2024, 62(4): 40-47. doi:10.6040/j.issn.1671-7554.0.2024.0036

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Objective To investigate the correlation between frailty and body composition among elderly patients with gastric cancer, so as to evaluate the efficacy of body composition metrics in forecasting frailty among this demographic. Methods Ninety-six elderly patients with gastric cancer underwent pathological diagnosis at the Affiliated Hospital of Weifang Medical University between September 2021 and August 2023. Utilizing the Fried frailty phenotype(FP), these patients were categorized into either the frailty group or the non-frailty group. Demographic data including age, sex, smoking history, alcohol consumption history, cancer location, cancer stage, body mass index(BMI), body fat content, and body fat percentage were collected for both groups of patients. The fat-free mass index(FFMI), muscle mass index(MMI), upper limb muscle mass index(ULMMI), and lower limb muscle mass index(LLMMI)were computed using the collected data. Univariate Logistic regression analysis was conducted to examine the relationship between these indices and frailty among elderly cancer patients. Subsequently, multivariate Logistic regression analysis was employed to determine if these indices served as independent factors influencing frailty in elderly cancer patients. Additionally, a ROC curve was constructed to assess the predictive capability of these indices for frailty in elderly patients with gastric cancer. Results (1)A total of 96 elderly patients with gastric cancer were included. The incidence of frailty in elderly patients with gastric cancer was 39.58 %. (2)The age and clinical stage of gastric cancer in the frailty group were higher than those of the non-fraity group(all P<0.05 ). (3)Body fat content and body fat percentage in the frailty group were higher than those in the non-frailty group, and FFMI, MMI, and LLMMI were significantly lower than those in the non-frailty group(all P<0.05). (4)Comparison of general data between the two groups revealed that age and clinical stages 3 and 4 of the tumor were associated with the occurrence of frailty in elderly patients with gastric cancer compared to clinical stage 1. Regarding the comparison of body composition between the two groups, FFMI, MMI, and LLMM were inversely correlated with frailty in elderly patients with gastric cancer, while body fat content and body fat percentage showed a positive correlation with frailty in this demographic. (5)After adjusting for age and cancer clinical stage, FFMI, MMI, LLMMI, body fat content, and body fat percentage emerged as independent predictors of frailty in elderly patients with gastric cancer. (6)The ROC curve analysis revealed that the AUC values for FFMI, MMI, LLMMI, body fat content, and body fat percentage were 0.701, 0.645, 0.655, 0.607, and 0.632, respectively. The combined AUC for all these indicators was calculated to be 0.833. Conclusion The detection rate of frailty among elderly patients with gastric cancer is notably high. The amalgamation of independent components within the human body composition holds significant predictive value in diagnosing frailty in this demographic. This approach aids in identifying high-risk groups vulnerable to frailty, thereby offering a theoretical foundation for prioritizing attention to frailty among elderly patients with gastric cancer.

Risk factors for death within 2 years in new maintenance haemodialysis patients

LI Jian, SUN Yun

Journal of Shandong University (Health Sciences). 2024, 62(4): 48-53. doi:10.6040/j.issn.1671-7554.0.2023.1106

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Objective To explore the risk factors for death within 2 years in patients newly admitted to maintenance haemodialysis(MHD). Methods The 2-year clinical data of patients who started haemodialysis from March 2019 to November 2020 in The Second Hospital, Cheeloo College of Medicine, Shandong University were retrospectively collected. They were divided into death group and survival group according to whether they had died at 2 years. The clinical data were compared and the risk factors for death were analyzed. The patients were grouped by pre-dialysis systolic blood pressure(SBP)to compare the impact of blood pressure. Finally, the independent risk factors for patient death were analyzed using univarite and mnltivariate Cox regression models. Results During the observation period, a total of 83 patients were newly admitted to MHD, 4 left within 2 years, and 3 received renal transplant. Of the 76 cases included, 17(22.4%)died. Compared with the survival group, patients in the death group had lower blood potassium, albumin, blood creatinine, and SBP at baseline, a higher proportion of comorbid coronary artery disease and diabetes mellitus, and a higher estimated glomerular filtration rate; patients with an SBP ≤140 mmHg(1 mmHg=0.133 kPa)had a higher case-fatality rate. Cox regression analysis revealed that the lower pre-dialysis SBP(HR=0.957, 95%CI: 0.928-0.987), albumin(HR=0.918, 95%CI: 0.857-0.984), and comorbid diabetes mellitus(HR=3.690, 95%CI: 1.157-11.768)were found to be independent risk factors for death in patients(P<0.05). Conclusion Newly admitted MHD patients have a high case-fatality rate; SBP≤140 mmHg suggests higher risk of death; lower pre-dialysis SBP, albumin, and comorbid diabetes mellitus are risk factors for their death within 2 years.

Effects of intense pulsed light on the meibomian gland and tear film lipid layer in patients with lipid deficiency dry eye disease

ZHANG Qichen, KANG Suifang, YIN Chuanjie, XIAO Juan, MA Guangfeng, CAO Yuan, CHEN Guoling

Journal of Shandong University (Health Sciences). 2024, 62(4): 54-60. doi:10.6040/j.issn.1671-7554.0.2024.0148

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Objective To observe the effects of intense pulsed light(IPL)on the meibomian gland and tear film lipid layer in patients with lipid deficiency dry eye disease. Methods A total of 60 patients(120 eyes)with lipid deficiency dry eye disease were divided into control group(60 eyes)and IPL group(60 eyes)using random numbers. Before and after 6 weeks of treatment, non-invasive breakup time(NIBUT), ocular surface disease index(OSDI)questionnaire, and corneal fluorescein staining(CFS)were assessed to evaluate the indicators of dry eye disease. The Oculus Keratograph analyzer and meibomian gland evaluator(MGE)were used to determine the meibomian gland dropout score(MGDS), meibomian gland yielding liquid secretion(MGLYS)and meibomian gland yielding secretion score(MGYSS)to assess the meibomian gland. The LipiView interferometer was used to evaluate the tear film lipid layer thickness(LLT). Results No statistically significant differences were observed between the two groups before treatment. Compared with baseline, NIBUT, OSDI, CFS, MGLYS, MGYSS and LLT were improved in both groups after treatment(all P<0.001), while there was no significant difference in MGDS. Except MGDS, the other parameters in the IPL group were improved better than those in control group after treatment(P_NIBUT=0.031, P_OSDI=0.023, P_CFS=0.014, P_MGLYS=0.020, P_MGLYS=0.023, P_LLT=0.004). No adverse reactions occurred during the treatment. Conclusion IPL could improve the function of meibomian gland and the thickness of tear film lipid layer; it is an effective and safe treatment for patients with lipid deficiency dry eye disease.

Application value of matrix-assisted laser desorption ionization time-of-flight mass spectrometry in the detection of drug resistance of Mycobacterium tuberculosis

LIU Chao, DIAO Tingting, ZHANG Hongji, LIU Hongwei, YANG Yongrui, LI Xiaofei

Journal of Shandong University (Health Sciences). 2024, 62(4): 61-67. doi:10.6040/j.issn.1671-7554.0.2024.0303

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Objective To explore the matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF-MS)platform for identifying Mycobacterium tuberculosis and detecting drug-resistant mutations and evaluate its application value. Methods MALDI-TOF-MS was used to detect three national reference strains, and the minimum detection limits for tuberculosis-specific identifying genes and drug-resistant mutations were determined. Respiratory tract clinical specimens of suspected tuberculosis patients were collected from January to September 2023 in the Tuberculosis Department of Kunming Third Peoples Hospital by non-random sampling method, including 120 sputum samples and 100 bronchoalveolar lavage fluid samples, with the content of 3-5 mL in each sample. Nucleic acid was extracted from all the samples, and the tuberculosis positive samples with Ct value≤32 were identified by qPCR kit for tuberculosis identification. The drug-resistant mutations of rifampicin(RIF), isoniazid(INH), ethambutol(EMB), moxifloxacin(MXF), streptomycin(SM)and pyrazinamide(PZA)were detected by MALDI-TOF-MS. The phenotypic drug susceptibility test(pDST)and third-generation sequencing(nanopore platfom)were used to detect the TB-positive samples, and the results were compared with those of MALDI-TOF-MS to verify its accuracy. Results The lowest detection limit of MALDI-TOF-MS was 60-100 CFU/mL for MTB identification genes IS6110 and ext_RD9, and 100-1 000 CFU/mL for drug-resistance mutations. A tolal of 132 tuberculosis positive samples with Ct value ≤ 32 were screened by qPCR. Compared with pDST results, the sensitivity, specificity and kappa value of MALDI-TOF-MS for detection of drug-resistant mutations were 93.75%, 100% and 0.96 for RIF, 98.33%, 90.28% and 0.88 for INH, 83.33%, 97.50% and 0.78 for EMB and 95.45%, 100% and 0.97 for MXF, respectively. Compared with nanopore sequencing, the sensitivity, specificity and kappa values of MALDI-TOF-MS for detection of drug-resistant mutations were 90.91%, 100% and 0.94 for RIF, 92.96%, 100% and 0.92 for INH, 92.86%, 100% and 0.96 for EMB, 95.45%, 100% and 0.97 for MXF, 95.74%, 100% and 0.97 for SM, 66.67%, 100% and 0.80 for PZA, respectively. Conclusion MALDI-TOF-MS can be used as an effective method for rapid detection of Mycobacterium tuberculosis drug-resistant mutations because its results were highly consistent with those of pDST and nanopore sequencing.

Umbilical cord mesenchymal stem cells sheets treated by small intestinal submucosa promote wound healing

SHEN Feifei, LI Dong, LIU Linghong, JU Xiuli

Journal of Shandong University (Health Sciences). 2024, 62(4): 68-77. doi:10.6040/j.issn.1671-7554.0.2024.0185

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Objective To explore the effect of extracellular matrix(ECM), especially the small intestinal submucosa(SIS)-treated umbilical cord mesenchymal stem cells(UC-MSCs)sheets on wound healing. Methods Primary UC-MSCs were isolated and cultured from umbilical cord tissues using the tissue block apposition method. Decellularized SIS was obtained using a chemical method, and recombinant human fibronectin(rFN), SIS, and Matrigel were immobilized on the surface of polystyrene(PS)cell culture dishes by physical adhesion. The effects of PS surface, rFN-PS surface, SIS-PS surface, and Matrigel-PS surface on the morphology of UC-MSCs were investigated, and the changes in gene expression were detected by RT-PCR, then changes in the secretion of extracellular vesicles(EVs)were detected using nanoparticle tracking analysis. Rat skin total excision wounds were treated with ECM-free, rFN-treated, SIS-treated, and Matrigel-treated UC-MSCs cell sheets, respectively, and the therapeutic effect was further verified by calculating the ratio of wound area to the original wound area. Results Compared with the PS surface, the morphology of UC-MSCs cultured on the SIS-PS surface was almost unaltered(P>0.05), and RT-PCR assay showed that gene expression of the SIS-PS surface-cultured UC-MSCs was enhanced, such as Nanog homeobox(NANOG, P=0.041), SRY-box transcription factor 2(SOX-2, P=0.009), octamer-binding transcription factor-4(OCT-4, P<0.001), interleukin-10(IL-10, P=0.049), indoleamine 2,3-dioxygenase(IDO, P=0.007), and transforming growth factor beta(TGF-β, P=0.046), meanwhile the ability of the SIS-PS surface-cultured UC-MSCs to secrete EVs was significantly increased(P<0.001). The results of the animal experiments revealed that the lowest percentage of wound to original wound area was 26.9%±6.1% in the group of animals treated with SIS-treated UC-MSCs cell sheets at day 7. Conclusion UC-MSCs cultured on the SIS-PS surface significantly improved immunosuppressive function and EVs secretion ability, and the corresponding cell sheets have a stronger ability to promote wound healing.

Pulmonary benign metastasizing leiomyoma: a report of 7 cases and literature review

WU Lin, SHI Chenxi, TONG Xing

Journal of Shandong University (Health Sciences). 2024, 62(4): 78-84. doi:10.6040/j.issn.1671-7554.0.2023.1148

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Objective To investigate the clinicopathological features, immunophenotype, pathogenesis, differentiation and management of pulmonary benign metastasizing leiomyoma(PBML). Methods The medical records and specimen data of 7 cases of PBML treated in the Department of Pathology, The First Affiliated Hospital of Soochow University during Aug. 2015 and Jan. 2022 were collected. All patients were female, aged 35 to 62 years(median 53 years), and all had a history of uterine leiomyoma surgery. The diagnosis was confirmed with chest CT, histopathology and immunohistochemistry. The imaging, pathological features and immunophenotypes were analyzed, and relevant literature was collected. Results CT images showed single or multiple quasi-circular hyperdense lesions of varying sizes. PBML was morphologically analogous to uterine leiomyoma. Immunohistochemically, all 7 cases were diffusely and strongly positive for Desmin and SMA. All 7 cases were ER positive, 4 cases were PR positive; 1 case had Ki-67 proliferation index of 10%, the other 6 had 1%-5%. All cases were negative for S-100, CD117, CD34 and HMB45. The diagnosis of this disease required a combination of history, imaging, pathology, and immunohistochemistry, and needed to be differentiated from leiomyosarcoma, fibroleiomyomatous hamartoma, inflammatory myofibroblastic tumor, and solitary fibrous tumor. The prognosis of PBML was generally favorable. Conclusion If CT images show single or multiple quasi-circular hyperdense lesions of varying sizes and the patient has a history of uterine fibroids or surgery, the possibility of PBML should be considered. Surgical resection is preferred for treatment.

Genetic analysis of two Chinese pedigrees with 3-M syndrome caused by CUL7 compound heterozygous variants

PENG Haiying, LIU Ailing, JI Xiangmei, WANG Yanyan, HE Yinlong, GAO Chunhai, MA Yuhua, LI lin

Journal of Shandong University (Health Sciences). 2024, 62(4): 85-91. doi:10.6040/j.issn.1671-7554.0.2024.0059

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Objective To explore the clinical features and genetic etiology of two Chinese pedigrees affected with 3-M(Miller-Mukusick-Malvaux)syndrome. Methods Two Chinese pedigrees with 3-M syndrome admitted to Linyi Peoples Hospital in September 2022 and June 2023 were selected as the research objects. Clinical data of the family members was collected, and the peripheral blood was selected for whole exome sequencing(WES)after informed consent. Candidate variants were verified by Sanger sequencing and pathogenicity assessment was conducted. Prenatal diagnosis was performed for high-risk fetuses in two pedigrees. Results The proband of pedigree 1 was 18-weeks pregnant with short stature, abnormal face and congenital dislocation of the hip at birth. WES detected compound heterozygous variants of CUL7 gene: c.4333C>T(p.R1445*), c.3291_3294del(p.H1098Cfs*42), inherited from the father and mother, respectively. The younger brother of the proband carried the same variants. According to the American Society for Medical Genetics and Genomics(ACMG)guidelines, both c.4333C>T and c.3291_3294del were judged to be pathogenic variants. The fetus carried the c.4333C>T variant. The proband from pedigree 2 showed short height, special face, scoliosis, pterygous scapular bone, bilateral oblique finger, short fifth finger, etc. The proband was found to harbor c.3823del(p.R1275Vfs*34)and c.758del(p.L253Rfs*2)compound heterozygous variants of CUL7 gene, which inherited from mother and father, respectively. And they were judged to be pathogenic variants and suspected pathogenic variants. Maternal prenatal diagnosis indicated that the fetus carried the c.758 del variant. Conclusion In this study, three patients with 3-M syndrome were diagnosed in two pedigrees. Two compound heterozygous variants of CUL7 gene were probably the genetic causes of pedigree 1 and pedigree 2, respectively. Above findings expanded the variation spectrum of CUL7 gene in 3-M syndrome and provided a basis for genetic counseling and prenatal diagnosis.

Differentiation and molecular pathological analysis of motor neurons in a case of spinal muscular atrophy

LIU Wenzhu, LIU Fuchen

Journal of Shandong University (Health Sciences). 2024, 62(4): 92-100. doi:10.6040/j.issn.1671-7554.0.2024.0118

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Objective To explore the molecular pathologic phenotype of spinal and bulbar muscular atrophy(SBMA)using motor neurons derived from induced pluripotent stem cells(iPSCs)from SBMA patients. Methods Skin fibroblasts from one SBMA patient and one healthy control were extracted and reprogrammed into iPSCs; iPSCs were induced into motor neurons progenitor(MNP)and differentiated into mature motor neurons(mMN); immunofluorescence staining was used to study cell proliferation and apoptosis, and the formation of intranuclear inclusion bodies was detected. Results The patient was a 35-year-old male who presented with proximal weakness of the extremities, hand tremors, and hypogonadism. Skeletal muscle biopsy showed pathologic changes of neurogenic damage. Peripheral blood capillary electrophoresis showed 44 repeats of CAG in exon 1 of the AR gene. iPSCs all expressed stemness markers, had normal karyotypes, and were able to differentiate randomly into trichodermal cell types. No intranuclear inclusion bodies were seen in patient iPSCs and MNP, but intranuclear inclusion bodies were more typical in mMN. Compared with normal controls, the patients MNP had an increased proportion of apoptosis and a decreased proportion of proliferation. Conclusion The iPSCs of SBMA patients carried pathogenic mutations, and their differentiated mMNs contained typical intranuclear inclusion bodies, which accurately mimicked the molecular pathological features of the disease and provided an ideal model for the subsequent mechanism study and drug target discovery.

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