Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

BACKGROUND:Cervical disc herniation can cause pain in the neck and shoulder area,as well as radiating pain in the upper limbs.The incidence rate is increasing year by year and tends to affect younger individuals.Fully understanding the biomechanical characteristics of the cervical spine in adolescents is of great significance for preventing and delaying the onset of cervical disc herniation in this age group. OBJECTIVE:To reconstruct cervical spine models for both healthy adolescents and adolescent patients with cervical disc herniation utilizing finite element analysis techniques,to analyze the motion range of the C1-T1 cervical vertebrae as well as the biomechanical characteristics of the annulus fibrosus,nucleus pulposus,endplates,and the cartilage of the small joints. METHODS:A normal adolescent's cervical spine and an adolescent patient with cervical disc herniation were selected in this study.The continuous scan cervical spine CT raw image data were imported into Mimics 21.0 in DICOM format.The C1-T1 vertebrae were reconstructed separately.Subsequently,the established models were imported into the 3-Matic software for disc reconstruction.The perfected models were then imported into Hypermesh software for meshing of the vertebrae,nucleus pulposus,annulus fibrosus,and ligaments,creating valid geometric models.After assigning material properties,the final models were imported into ABAQUS software to observe the joint motion range of the C1-C7 cervical vertebrae segments under different conditions,and to analyze the biomechanical characteristics of the annulus fibrosus,nucleus pulposus,endplates,and small joint cartilage of each cervical spine segment. RESULTS AND CONCLUSION:(1)In six different conditions,the joint motion range of the C1 vertebra in the cervical spine models of both normal adolescent and adolescent patient with cervical disc herniation was higher than that of the other vertebrae.Additionally,the joint motion range of each cervical spine segment in normal adolescent was greater than that in adolescent patient with cervical disc herniation.(2)In the cervical spine model of normal adolescent,the maximum stress values in the annulus fibrosus and nucleus pulposus were found on the left side during C2-3 flexion conditions(0.43 MPa and 0.17 MPa,respectively).In the cervical spine model of adolescent patient with cervical disc herniation,the maximum stress values were found on the left side during C7-T1 flexion conditions(0.54 MPa and 0.18 MPa,respectively).(3)In the cervical spine model of normal adolescent,the maximum stress value on the endplate was found on the left side of the upper endplate of C3 during flexion conditions(1.46 MPa).In the model of adolescent patient with cervical disc herniation,the maximum stress value on the endplate was found on the left side of the lower endplate of C7 during flexion conditions(1.32 MPa).(4)In the cervical spine model of normal adolescent,the maximum stress value in the small joint cartilage was found in the C2-3 left rotation conditions(0.98 MPa).In adolescent patient with cervical disc herniation,the stress in the small joint cartilage significantly increased under different conditions,especially in C1-2,with the maximum stress found during left flexion(3.50 MPa).(5)It is concluded that compared to normal adolescent,adolescent patient with cervical disc herniation exhibits altered cervical curvature and a decrease in overall joint motion range in the cervical spine.In adolescent with cervical disc herniation,there is a significant increase in stress on the annulus fibrosus,nucleus pulposus,and endplates in the C7-T1 segment.The stress on the left articular cartilage of the C1-2 is notable.Abnormal cervical curvature may be the primary factor causing these stress changes.

Aim To predict and validate the mechanism of wenshen xuanbi tang(WSXBT) in treatment of osteoporosis (OP) based on network pharmacology, molecular docking techniques and in vivo experimental techniques. Methods Network pharmacology was used to screen the key ingredients and core targets of WSXBT for the treatment of osteoporosis. Metascape database was used for gene ontology (GO) biological process enrichment analysis and kyoto encyclopedia of genes and genomes (KEGG) signaling pathway enrichment analysis of core targets. AutoDockTools 1. 5. 7 software was applied in molecular docking to simulate the binding activity of key active ingredients to core targets. To study the efficacy of WSXBT on rats with osteoporosis and to verify the related targets and pathways, rat models of osteoporosis were established by excising the bilateral ovaries of rats. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum OPG, PINP and RANKL content. Biomechanical tester was applied to test the biomechanics of rat femurs. Micro-CT was applied to detect the femoral bone density. Then, Western blot was employed to measure the protein expression levels of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt). Results A total of 156 active ingredients of WSXBT were screened, involving 229 potential targets, 23 core targets and 145 signaling pathways. The molecular docking results showed that five key ingredients, including quercetin, kaempferol, naringenin, isobavachin and licochalcone a, possessed good binding ability to the core targets of PIK3R1 and AKT1. The results of in vivo experiments showed that WSXBT could significantly increase bone density, improve bone tissue microstructure, enhance femur biomechanics and increase PINP expression and OPG/RANKL ratio in rats with osteoporosis. Results of WB showed that WSXBT significantly increased p-PI3K/PI3K and p-Akt/Akt ratios. Conclusions WSXBT could improve bone mineral density in postmenopausal osteoporotic rats through PI3K/ Akt signaling pathway and increasing OPG/RANKL ratio.

Objective To observe the clinical efficacy of thumb-tack needling for subcutaeous embedding combined with joint mobilization in the treatment of post-stroke shoulder-hand syndrome.Methods A total of 80 patients with post-stroke shoulder-hand syndrome were randomly divided into a treatment group and a control group,with 40 patients in each group.Both groups were given arthrocentesis,the control group was given ordinary acupuncture on the basis of arthrocentesis,and the treatment group was combined with thumb-tack needling for subcutaeous embedding.One course of treatment was 4 weeks and a total of 4 weeks of treatment was given.After 1 month of treatment,the clinical efficacy of the two groups was evaluated.The changes of Visual Analogue Scale(VAS)of pain scores and simplified Fugl-Meyer Assessment(FMA)scores,as well as the pain-free passive forward flexion and abduction of the shoulder joint of the affected limb were observed before and after treatment.The Simple Quality of Life Scale(SF-36)scores of the patients in the two groups were compared after treatment.The safety and the occurrence of adverse reactions in the two groups were also evaluated.Results(1)The total effective rate was 95.00%(38/40)in the treatment group and 80.00%(32/40)in the control group.The efficacy of the treatment group was superior to that of the control group,and the difference was statistically significant(P＜0.05).(2)After treatment,the VAS scores and upper extremity FMA scores of the patients in the two groups were significantly improved(P＜0.05),and the treatment group was significantly superior to the control group in improving the VAS scores and upper extremity FMA scores,and the differences were statistically significant(P＜0.05).(3)After treatment,the joint mobility of patients in the two groups were significantly improved(P＜0.05),and the improvement of shoulder joint movement in the treatment group was superior to that in the control group,and the difference was statistically significant(P＜0.05).(4)After treatment,the SF-36 Quality of Life Scale scores of the treatment group were significantly superior to those of the control group in terms of physical function,psychological function,emotional health,and social function levels,and the difference was statistically significant(P＜0.05).(5)There was no significant difference in the incidence of adverse reactions between the treatment group and the control group(P＞0.05).Conclusion Thumb-tack needling for subcutaeous embedding combined with joint mobilization exert certain effect in the treatment of post-stroke shoulder-hand syndrome.It can significantly improve the pain symptoms of patients,thus improving their quality of life,and the clinical effect is remarkable.

Ankylosing spondylitis (AS) combined with lower cervical fracture is often categorized into unstable fracture, with a high incidence of neurological injury and a high rate of disability and morbidity. As factors such as shoulder occlusion may affect the accuracy of X-ray imaging diagnosis, it is often easily misdiagnosed at the primary diagnosis. Non-operative treatment has complications such as bone nonunion and the possibility of secondary neurological damage, while the timing, access and choice of surgical treatment are still controversial. Currently, there are no clinical practice guidelines for the treatment of AS combined with lower cervical fracture with or without dislocation. To this end, the Spinal Trauma Group of Orthopedics Branch of Chinese Medical Doctor Association organized experts to formulate Clinical guidelines for the treatment of ankylosing spondylitis combined with lower cervical fracture in adults ( version 2024) in accordance with the principles of evidence-based medicine, scientificity and practicality, in which 11 recommendations were put forward in terms of the diagnosis, imaging evaluation, typing and treatment, etc, to provide guidance for the diagnosis and treatment of AS combined with lower cervical fracture.

OBJECTIVE To explore the safety and efficacy of tocilizumab in the treatment of refractory anti-N-methyl-D-aspartate receptor encephalitis in children, and to provide reference for the treatment of this disease. METHODS The clinical manifestations, diagnosis and treatment, safety and efficacy of tocilizumab in a case of refractory anti-NMDAR encephalitis in Children’s Hospital, Zhejiang University School of Medicine were analyzed retrospectively, and the relevant literature was reviewed. RESULTS The clinical symptoms of the patient were not improved after 2 doses of methylprednisolone, immunoglobulin and 6 doses of rituximab. After 6 doses of tocilizumab, the modified Rankin scale(mRS) score was improved without adverse reactions. CONCLUSION Tocilizumab, as a escalation second-line immunotherapy, is effective and well tolerated in the treatment of refractory anti-NMDAR encephalitis. It is one of the potential therapeutic means.

Objective Vascular dementia(VD)is a clinical syndrome caused by various cerebrovascular diseases,including ischemic,hemorrhagic,and acute and chronic hypoxic cerebrovascular diseases,leading to impaired brain function and affecting patients'cognitive ability,daily life,and work abilities.Vascular dementia is a preventable and reversible form of dementia,second only to Alzheimer's disease as the second common cause of dementia.At present,the relevant pathogenesis of vascular dementia is not clear,and there is no clear treatment method.However,its pathogenesis may be related to neuroinflammation,oxidative stress,neuronal damage and white matter lesions.Its main risk factors include genetic factors,hypercholesterolemia,diabetes,hypertension,etc.Neuroinflammatory response plays a major role in the process of secondary brain injury caused by cerebral ischemia,and inflammatory factors lead to an inflammatory cascade reaction that exacerbates damage to the nervous system.Inhibiting the inflammatory pathway and reducing the expression of inflammatory factors can improve the symptoms of vascular dementia patients and animal models,indicating that neuroinflammation may play an important role in the pathogenesis of vascular dementia.This article explores the effects of Buyang Huanwu Decoction on inflammatory factors from the perspective of summarizing relevant literature in recent years.It mainly reviews the pharmacological effects of Buyang Huanwu Decoction on treating vascular dementia,the relationship between inflammatory factor levels and vascular dementia,and the prevention and treatment of vascular dementia by regulating inflammatory factor levels.

Objective To evaluate the bioequivalence of the vardenafil hydrochloride tablets in fasting and fed conditions in healthy Chinese adult subjects with the test and reference formulations.Methods A randomized,open,single-dose,two-preparation,two-sequence,two-period,crossover design was used,and 40 healthy male subjects enrolled in the fasting state and 66 healthy male subjects enrolled in the fed state.The trial was conducted in two cycles,with 20 mg of either the subject formulation or the reference formulation,vardenafil hydrochloride tablets,being administered in each cycle.The drug concentration of vardenafil in plasma was determined by the liquid chromatography-tandem mass spectrometry(LC/MS-MS)method.Pharmacokinetic parameters were calculated using the non-compartment model,and the safety evaluation indexes were statistically analyzed using SAS 9.4 or above version program data statistical software.Results Arithmetic mean values of the main pharmacokinetic parameters of the subject formulation of vardenafil hydrochloride tablets and the reference formulation in the fasting state:Cmaxwere(34.94±18.33)and(36.69±19.45)ng·mL-1;AUC0-t were(74.38±34.11)and(74.25±33.37)ng·mL-1·h;AUC0-∞ were(76.70±34.36)and(76.46±33.84)ng·mL-1·h,respectively.Arithmetic mean values of the main pharmacokinetic parameters of the subject formulation of vardenafil hydrochloride tablets and the reference formulation in the fed state:Cmax were(22.84±12.48)and(21.68±11.12)ng·mL-1;AUC0_twere(70.82±35.88)and(72.71±34.63)ng·mL-1·h;AUC0-∞ were(73.48±36.44)and(75.29±35.12)ng·mL-1·h,respectively.The 90％confidence intervals for the geometric mean ratios of the main pharmacokinetic parameters such as Cmax,AUC0-t and AUC0-∞ of the prototype drug vardenafil in plasma after oral administration of 20 mg of the test and reference formulations of vardenafil tablets to the subjects in fasting and postprandial states fell within the equivalence interval of 80.00％to 125.00％.Conclusion The subject formulation of vardenafil hydrochloride tablets was bioequivalent to the reference formulation in fasting and fed conditions in healthy Chinese subjects.

Following the principles of evidence-based medicine,in accordance with the structure and drafting rules of standardized documents,based on literature research,according to the characteristics of chronic cough in children and issues that need to form a consensus,the TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children was formulated based on the Delphi method,expert discussion meetings,and public solicitation of opinions.The guideline includes scope of application,terms and definitions,eti-ology and diagnosis,auxiliary examination,treatment,prevention and care.The aim is to clarify the optimal treatment plan of Chinese medicine in the diagnosis and treatment of this disease,and to provide guidance for improving the clinical diagnosis and treatment of chronic cough in children with Chinese medicine.

Di-(2-ethylhexyl) phthalate (DEHP) is currently one of the most widely used plasticizers, widely found in all kinds of items, such as children’s toys and food packaging materials, but also added to wallpaper, cable protective agents and other building decoration materials. DEHP is toxic and absorbed by the human body through respiratory tract, digestive tract and skin contact, which can cause damage to multiple systems, especially the male reproductive system, and testis is an important target organ. Oxidative stress injury is the core mechanism of spermatogenesis disorder caused by DEHP. DEHP exposure can cause oxidative stress or reactive oxygen species (ROS) increase in germ cells, and on this basis, promote cell apoptosis or cause excessive autophagy. The toxicity of DEHP to Leydig cells is mainly to interfere with the synthesis of steroid hormones. For Sertoli cells, ferroptosis and destruction of the blood-testis barrier are common injury mechanisms. In addition, gene methylation caused by DEHP not only affects the spermatogenic process, but also has epigenetic effects on offspring. In this paper, we reviewed the pathological damage, germ cell toxicity and epigenetic effects of DEHP on testis, and focused on the damage and molecular mechanism on testicular spermatogenic cells, Leydig cells and Sertoli cells. Future research is required to elucidate the body’s clearance mechanism and treatment plan after exposure to DEHP and whether DEHP will damage the function of myoid cells. It is hoped that this can provide new ideas for prevention and treatment of male reproductive disorders resulting from long-term exposure to plastic products.