Amyotrophic lateral sclerosis (ALS) is an irreversible, fatal neurodegenerative disorder whose incidence is positively correlated with the aging population. ALS is characterized by the progressive loss of motor neurons, leading to muscle weakness, atrophy, and ultimately respiratory failure. The pathogenesis of ALS involves multiple factors, including genetic and environmental influences, with genetic factors playing a particularly significant role. To date, several causative genes have been identified in ALS, such as the Cu/Zn superoxide dismutase 1 (Cu/Zn SOD1, also known as SOD1) gene, transactive response DNA-binding protein 43 (TDP-43) gene, fused in sarcoma (FUS) gene, and chromosome open reading frame 72 (C9orf72). Mutations in these genes have been found not only in familial ALS but also in sporadic ALS. Based on the identified ALS risk genes, various ALS animal models have been established through multiple approaches, including transgenic models, gene knockout/knock-in models, and adeno-associated virus-mediated overexpression models. These models simulate some typical pathological features of human ALS, such as motor neuron loss, ubiquitinated inclusions, and neuromuscular junction degeneration. However, these models still have limitations: (1) single-gene mutation models are insufficient to fully replicate the complex multi-factorial pathogenesis of sporadic ALS; (2) significant differences in microenvironmental regulation mechanisms and the rate of neurodegeneration between model organisms and humans may affect the accurate reproduction of disease phenotypes and the reliable evaluation of drug efficacy. To better understand the pathogenesis of ALS and promote the development of effective therapies, constructing and optimizing ALS animal models is crucial. This review aims to summarize commonly used ALS gene mutation mouse models, analyze their phenotypes and pathological characteristics, including transgenic mouse models, gene knockout/knock-in mouse models, and adeno-associated virus-mediated overexpression mouse models, and further discuss their specific applications in ALS pathogenesis research and drug development by comparing the advantages and limitations of each model.

Amyotrophic lateral sclerosis (ALS) is an irreversible, fatal neurodegenerative disorder whose incidence is positively correlated with the aging population. ALS is characterized by the progressive loss of motor neurons, leading to muscle weakness, atrophy, and ultimately respiratory failure. The pathogenesis of ALS involves multiple factors, including genetic and environmental influences, with genetic factors playing a particularly significant role. To date, several causative genes have been identified in ALS, such as the Cu/Zn superoxide dismutase 1 (Cu/Zn SOD1, also known as SOD1) gene, transactive response DNA-binding protein 43 (TDP-43) gene, fused in sarcoma (FUS) gene, and chromosome open reading frame 72 (C9orf72). Mutations in these genes have been found not only in familial ALS but also in sporadic ALS. Based on the identified ALS risk genes, various ALS animal models have been established through multiple approaches, including transgenic models, gene knockout/knock-in models, and adeno-associated virus-mediated overexpression models. These models simulate some typical pathological features of human ALS, such as motor neuron loss, ubiquitinated inclusions, and neuromuscular junction degeneration. However, these models still have limitations: (1) single-gene mutation models are insufficient to fully replicate the complex multi-factorial pathogenesis of sporadic ALS; (2) significant differences in microenvironmental regulation mechanisms and the rate of neurodegeneration between model organisms and humans may affect the accurate reproduction of disease phenotypes and the reliable evaluation of drug efficacy. To better understand the pathogenesis of ALS and promote the development of effective therapies, constructing and optimizing ALS animal models is crucial. This review aims to summarize commonly used ALS gene mutation mouse models, analyze their phenotypes and pathological characteristics, including transgenic mouse models, gene knockout/knock-in mouse models, and adeno-associated virus-mediated overexpression mouse models, and further discuss their specific applications in ALS pathogenesis research and drug development by comparing the advantages and limitations of each model.

Chemical reference material(CRM)is an important material basis in the process of chemical drug research and development and quality control.This paper introduces the definition and classification of CRMs;the domestic and international regulations and guidelines for the research and development,production,management and use of CRMs by pharmaceutical companies and authoritative CRM issuing organizations;the common preparation methods and key technologies of CRM raw materials;and the technical requirements for the selection of raw materials for different types of CRMs.In addition,this paper also introduces the routine development process and data requirements for the candidate raw material to become a CRM after chemical structure verification,physical and chemical property analysis,homogeneity assessment,stability monitoring,and assignment.It also introduces the classical assignment method,mass balance method,in detail,to provide users of CRMs and the developers of new drugs with some technical references related to the development,application and management of CRMs in China.

Objective:To analyze the gene mutation type and clinical phenotype of patients with PRRT2 mutation, and explore their relations with prognosis. Methods:A total of 18 patients with PRRT2 gene mutation (1 patient with novel mutation in PRRT2 gene, and 17 probands in 17 families with PRRT2 gene mutation) were enrolled in Department of Neurology, First Affiliated Hospital of Air Force Medical University from January 2018 to July 2023. Serum of the patients was collected for whole exon sequencing, and mutation sites and types of PRRT2 gene were analyzed. SWISS-MODEL website was used to predict the changes in protein structure caused by PRRT2 gene mutation. The relations of gene mutation type and clinical phenotype with prognosis of these patients were analyzed. Results:(1) All 18 patients with PRRT2 gene mutation were heterozygous mutation, including 12 frameshift mutations, 5 missense mutations, and 1 integer mutation. The clinical phenotype included benign familial infantile epilepsy (BFIE) in 5 patients, epilepsy in 6 patients, exercise-induced paroxysmal kinesigenic dyskinesia (PKD) in 5 patients, and infantile convulsion and choreoathetosis (ICCA) in 2 patients. A total of 8 mutation sites were found in 18 patients with PRRT2 gene mutation, of which 3 mutation sites have been reported, and 5 mutation sites have not been reported, including c.647(exon2)C>A, c.647(exon2)C>G, c.170(exon2)delC, c.981(exon3)C>G, and lossl(EXON: 2)(all). (2) Eighteen patients mainly accepted oxcarbazepine, levetiracetam, and sodium valproate in combination or monotherapy. Among them, 5 BFIE patients, 2 ICCA patients and 3 epilepsy patients were seizure-free after treatment. PKD patients did not respond well to oxcarbazepine. (3) Three frameshift mutations (mutation sites: c.649 [exon2]_c.650 [exon2] insC, c.640 [exon2]_c.641 [exon2] insC, and c.170 [exon2] delC) led to premature termination of protein translation, resulting in significant changes in protein structure. Four missense mutations (mutation sites: c.640[exo2]G>C, c.647[exon2]C>A, c.647[exon2]C>G, and c.981[exon3]C>G) had little effect on protein structure changes. No relation was found between changes of protein structure caused by different mutation types and prognosis. Conclusion:PRRT2 gene mutation patients with clinical phenotypes of BFIE and ICCA have good prognosis, but the mutation type is not related with the prognosis of patients.

Objective:To investigate the study on the diagnostic value of multimodal ultrasound technique for the lesion of extensor carpi ulnaris(ECU)tendon in patients with rheumatoid arthritis(RA).Methods:A total of 175 RA patients who were confirmed by the department of rheumatology of Yantaishan Hospital of Yantai city from December 2021 to January 2023 were selected,and them were included into the RA group.Other 50 patients without RA but with clinical symptoms of wrist were included into the non-RA group,and 50 healthy volunteers were included into the healthy control group.All subjects underwent routine ultrasound and shear wave elastography(SWE)examination on wrist,and then,the characteristics of ultrasound images of wrists and the blood flow distribution of ECU power Doppler ultrasonography(PDUS)were recorded.SWE was used to measure ECU to obtain elastic modulus index(EI)and velocity modulus index(VI).The differences between three groups were compared,and the receiver operating characteristic(ROC)value of RA patients were drawn,so as to confirm the area under curve(AUC)value and optimize cutoff value.Results:There were significant differences in EI and VI of the ECU tendon among three groups(F=61.15,61.28,P<0.05),respectively.The optimal cut-off values of EI and VI were respectively 319.35 kPa and 10.55 m/s in RA patients.In RA patients,age and disease course had significant influences on EI(r=0.19,0.21,P<0.05),and age,disease course,ultrasound score of wrist joint,and grade of power Doppler ultrasonography PDUS of the ECU tendon(ECUPDUS)had significant influences on VI(r=0.19,0.15,-0.16,-0.17,P<0.05).Conclusion:SWE is able to quantitatively and non-invasively assess the stiffness information of the ECU tendon in RA patients.After the supplement of gray-scale ultrasound and PDUS,multimodal ultrasound technique can clearly judge the correlation of the lesions of ECU tendon of RA patients.

Objective:To explore the differences in clinicopathological features, survival status and prognostic influencing factors of breast cancer patients with different molecular subtypes, and to provide bases for the prevention and treatment of breast cancer.Methods:The clinicopathological data of new-onset female breast cancer patients hospitalized in Shanxi Province Cancer Hospital from January 2015 to December 2016 were retrospectively analyzed, and patients were followed up. The clinicopathological features of patients with different molecular subtypes were compared. The follow-up was performed until June 30, 2021. Kaplan-Meier method was used to analyze the survival of patients, and Cox proportional hazards model was used to analyze the factors affecting overall survival (OS) of patients with different molecular subtypes.Results:There were 272 (14.9%), 1 005 (55.2%), 277 (15.2%) and 268 (14.7%) patients with subtypes of Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2) overexpression and triple-negative breast cancer (TNBC), respectively. The differences in the distribution of patients with age at diagnosis, age at menarche, menopausal status, age at menopause, pathological type, longest tumor diameter, T staging, N staging, histological grading, and TNM staging were statistically significant among the four groups (all P < 0.05). At a median follow-up of 60 months, the 5-year OS rates of Luminal A, Luminal B, HER2 overexpression and TNBC subtypes were 93.8%, 89.2%, 77.6% and 78.0%, respectively, and the difference was statistically significant ( χ2 = 58.76, P < 0.001). M staging was an independent influencing factor for OS in patients with Luminal A breast cancer ( HR = 16.789, 95% CI 4.972-56.690, P < 0.001); T staging ( HR = 2.721, 95% CI 1.715-4.319), N staging ( HR = 4.460, 95% CI 2.399-8.291) and M staging ( HR = 3.364, 95% CI 1.988-6.670) were independent influencing factors for OS in patients with Luminal B breast cancer (all P < 0.001); N staging ( HR = 4.428, 95% CI 1.836-10.677) and M staging ( HR = 13.489, 95% CI 6.043-30.107) were independent influencing factors for OS of patients with HER2 overexpression breast cancer (both P < 0.01); T staging ( HR = 3.052, 95% CI 1.575-5.915), N staging ( HR = 2.492, 95% CI 1.298-4.785) and M staging ( HR = 33.012, 95% CI 8.606-126.637) were independent influencing factors for OS of patients with TNBC (all P < 0.01). Conclusions:The clinicopathological features and prognostic influencing factors of breast cancer patients with different molecular subtypes are different, and the prognosis of HER2 overexpression and TNBC patients is poor. Clinicians should provide individualized treatment and follow-up programs for patients with different molecular subtypes of breast cancer.

Objective:To investigate psychological resilience of inpatients with extracranial arteriovenous malformation (AVM) and analyze the related factors, in order to provide scientific basis for improving the psychological resilience of patients.Methods:A cross-sectional study was conducted to include patients with extracranial AVM who were hospitalized in the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from October 2020 to December 2021. The general information questionnaire, Cornor-Davidon resilience scale, Herth hope index, medical coping modes questionnaire and family APGAR scale were used to investigate them. SPSS 21.0 software was used. The t-test, one-way ANOVA, Pearson correlation analysis and multiple linear regression analysis were used for statistical analysis. Results:In total, 177 patients with extracranial AVM were included in our study. The total mean score of the resilience scale was 65.94±13.90, and the mean scores of the three dimensions of resilience, optimism and strength were 33.02±7.67, 10.38±2.75 and 22.54±4.67. The mean scores of Herth hope index was 37.50±3.56, positive coping style was 24.89±6.65, and family APGAR scale was 8.19±2.41. In univariate analysis, gender, ethnicity and family relationship had significant differences in psychological resilience (all P<0.05). Among these patients, female’s mental resilience score was significantly lower than that of male’s. Correlation analysis showed that the scores of the Herth hope index, positive coping style, and family APGAR scale were positively correlated with the total scores of resilience and the scores of each dimension (all P<0.01). Multiple linear regression analysis showed that gender, the scores of Herth hope index, positive coping mode, family APGAR scale were main influencing factors of resilience ( P<0.05). Conclusion:Female patients with extracranial AVM need more attention to their psychological problems and psychological reactions. Herth hope, positive coping mode, family-centered care are the protective factors of resilience of patients with extracranial AVM.

Objective:To investigate psychological resilience of inpatients with extracranial arteriovenous malformation (AVM) and analyze the related factors, in order to provide scientific basis for improving the psychological resilience of patients.Methods:A cross-sectional study was conducted to include patients with extracranial AVM who were hospitalized in the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from October 2020 to December 2021. The general information questionnaire, Cornor-Davidon resilience scale, Herth hope index, medical coping modes questionnaire and family APGAR scale were used to investigate them. SPSS 21.0 software was used. The t-test, one-way ANOVA, Pearson correlation analysis and multiple linear regression analysis were used for statistical analysis. Results:In total, 177 patients with extracranial AVM were included in our study. The total mean score of the resilience scale was 65.94±13.90, and the mean scores of the three dimensions of resilience, optimism and strength were 33.02±7.67, 10.38±2.75 and 22.54±4.67. The mean scores of Herth hope index was 37.50±3.56, positive coping style was 24.89±6.65, and family APGAR scale was 8.19±2.41. In univariate analysis, gender, ethnicity and family relationship had significant differences in psychological resilience (all P<0.05). Among these patients, female’s mental resilience score was significantly lower than that of male’s. Correlation analysis showed that the scores of the Herth hope index, positive coping style, and family APGAR scale were positively correlated with the total scores of resilience and the scores of each dimension (all P<0.01). Multiple linear regression analysis showed that gender, the scores of Herth hope index, positive coping mode, family APGAR scale were main influencing factors of resilience ( P<0.05). Conclusion:Female patients with extracranial AVM need more attention to their psychological problems and psychological reactions. Herth hope, positive coping mode, family-centered care are the protective factors of resilience of patients with extracranial AVM.

Objective:To investigate the association between breast cancer and thyroid diseases, and to provide evidence for the prevention and treatment of thyroid diseases in breast cancer patients.Methods:A total of 511 newly diagnosed breast cancer patients were recruited between March 2018 and August 2019 from Shanxi Province Cancer Hospital, and 303 age-matched newly diagnosed breast benign disease patients and 341 age-matched healthy controls were recruited during the same time-frame. Thyroid B-ultrasound and thyroid function test were performed in the three groups. By reviewing the medical records, the general and clinicopathological data of the patients were collected, and the differences in the prevalence of thyroid diseases among the three groups were compared. The changes of thyroid function in breast cancer patients before treatment, in the middle stage of chemotherapy and at the end of chemotherapy were compared.Results:Among breast cancer group, breast benign disease group and healthy control group, the differences in the prevalence rates of hypothyroidism [32.5% (166/511), 25.7% (78/303) and 21.7% (74/341)], thyroid nodules [50.7% (259/511), 43.2% (131/303) and 41.6% (142/341)] and Thyroid Imaging Reports and Data System(TI-RADS) grade 4 and above thyroid nodules [15.4% (40/259), 14.5% (19/131) and 4.9% (7/142)] were statistically significant (all P < 0.05). The abnormal rates of thyroid stimulating hormone (TSH) and free thyroxine (fT4) in breast cancer group were higher than those in breast benign disease group and healthy control group [34.1% (174/511) vs. 26.1% (79/303), 23.5% (80/341); 24.9% (127/511) vs. 8.6% (26/303), 3.2% (11/341)], and the differences were statistically significant (both P < 0.05). The levels of fT4, free three iodide thyroxine (fT3), thyroid immunoglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) in breast cancer patients before treatment, in the middle stage of chemotherapy and at the end of chemotherapy were statistically different (all P < 0.05). The abnormal rates of fT4, TgAb and TPOAb in the last chemotherapy cycle were lower than those before chemotherapy [11.5% (59/511) vs. 24.9% (127/511), 5.1% (26/511) vs. 17.4% (89/511), 11.9% (61/511) vs. 20.4% (104/511)] in breast cancer patients, and the differences were statistically significant (all P < 0.001). Conclusions:The breast cancer is associated with thyroid diseases. Clinicians should pay more attention to the changes of thyroid diseases and thyroid function during the treatment and in the follow-up process of breast cancer patients, so as to detect the thyroid diseases early and carry out standardized treatment.

Objective:To explore the clinicopathological characteristics and factors influencing the survival of young breast cancer patients with diagnostic age below 35 years, and to provide the basis for the prevention and treatment of young breast cancer patients.Methods:Epidemiological and clinicopathological data of young female patients with newly diagnosed breast cancer from Shanxi Province Cancer Hospital between January 2015 and December 2016 were retrospectively analyzed. The data included age at diagnosis, reproductive history, history of abortion, menopausal status, and immunohistochemical results. Univariate and multivariate analysis were performed by using Cox regression model.Results:A total of 118 young breast cancer patients were collected, and the median age was 31 years old. Among them, the vast majority of 118 young breast cancer patients were invasive cancer (113 cases, accounting for 95.8%); there were 65 cases (55.1%) with tumor diameter ≤ 20 mm, 61 cases (51.7%) at N 0 stage, and 112 cases (94.9%) at M 0 stage. The positive rates of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) were 73.7% (87/118), 69.5% (82/118) and 28.8% (34/118), respectively. Luminal B breast cancer was the predominant molecular subtype, accounting for 55.1% (65/118). By the end of follow-up (median follow-up period of 60 months), the overall survival rate of young breast cancer patients was 78.8%. Multivariate analysis showed that TNM staging was an independent factor affecting overall survival in young breast cancer patients ( HR = 7.858, 95% CI 2.924-21.120, P < 0.001). Conclusions:Young breast cancer patients have unique clinicopathological features and TNM staging is an independent factor affecting the prognosis. Individualized treatment helps to improve the quality of life and prolong the survival time of patients.