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.

ObjectiveTo analyze the epidemiological characteristics and influencing factors of clustered influenza-like illness (ILI) outbreaks in Yangpu District, Shanghai from 2012 to 2022, and to provide a scientific basis for formulating specific prevention and control measures of influenza in this district. MethodsData on clustered ILI outbreaks from 2012 to 2022 were collected, and the epidemiological pattern of the cluster outbreaks of influenza and its influencing factors of prevalence and duration were explored using statistical methods such as descriptive epidemiology, χ² test and logistic regression analysis. ResultsA total of 60 clustered ILI outbreaks were reported in Yangpu District, Shanghai from 2012 to 2022, with a cumulative number of 543 cases and an annual average incidence rate of 16.96%. The male-to-female ratio was1.06∶1. The largest number of ILI were reported in 2019, mainly from November to January of the next year, with December being the peak of outbreaks. The Streets of Changhai Rd. in Yangpu District had the largest number of reported outbreaks, accounting for 30.00% of the total outbreaks. Influenza cluster outbreaks occurred in schools, with the majority of outbreaks and cases reported in primary schools (accounting for 65.00% and 62.06% of the total, respectively). The outbreaks were mainly caused by influenza B virus, accounting for 50% of the total number of outbreaks. The prevalence rate of influenza cluster outbreaks varied among different schools in terms of their affiliated streets, school attributes and school types, with those in Kongjiang Rd. Subdistrict, private schools, and childcare institutions being relatively high. The duration of outbreaks reported for >2 days was longer than those reported for ≤2 days (OR=8.604, 95%CI: 1.509–49.067). ConclusionThe ILI outbreaks in Yangpu District present a seasonal pattern, with primary schools and Changhai Rd. Street as the targeted places for implementing prevention and control measures. Timely detection and reporting and active disposal can prevent a further spread of the outbreaks.

The field of post-marketing benefit-risk assessment for traditional Chinese medicine（TCM） is still in its nascent stage， lacking a universally accepted and cohesive evaluation framework and standards. This study presented a strategy developed for the benefit-risk assessment of post-marketing of TCM， and explored the critical techniques and specific implementation steps involved in the assessment process. Initially， appropriate qualitative assessment frameworks and quantitative analysis models were selected for the integrated qualitative and quantitative benefit-risk assessment. Subsequently， key technologies were outlined， including the establishment of a benefit-risk indicator system， the assignment of indicator weights， and the definition of criteria attributes. Furthermore， the implementation steps were elaborated， which involved defining decision-making issues， data collection， evaluation methodologies， variability factors， and sensitivity analysis. Finally， a case study of the benefit-risk assessment of a TCM injection for hepatitis B treatment was conducted to validate the feasibility of the proposed strategy. The objective of this research was to provide theoretical support and practical references for the development of a comprehensive post-marketing benefit-risk assessment system for TCM.

OBJECTIVE To establish a closed-loop management system for the whole-process traceability of outpatient drugs based on internet of things （IoT） and blockchain technology， and evaluate its implementation effects. METHODS A closed-loop management system for the whole-process traceability of outpatient drugs covering the entire drug lifecycle was designed using drug traceability codes integrated with IoT and blockchain technology. System effectiveness was evaluated from three dimensions： work efficiency， medication management quality and data safety by comparing indicators such as the acceptance time of incoming drugs and the number of collected drug traceability codes before the system implementation （October to December 2024） and after the system implementation （January to March 2025）. RESULTS A closed-loop management system for the whole-process traceability of outpatient drugs， centered around the drug traceability code management system， was successfully established. The acceptance time for incoming drugs was shortened from （4.65±0.26） h before implementation to （0.34±0.08） h after implementation （P＜ 0.05）. The number of collected drug traceability codes increased from 419 018 to 1 236 522， and the coverage rate of traceability codes rose from 28.36% to 89.88% （P＜0.05）. The time pharmacists spent on drug expiry management per week decreased from （128.40±19.20） min to （0.56±0.13） min （P＜0.05）， and the dispensing time for a single prescription （excluding a part of injections and repackaged drugs） was reduced from （143.25±17.67） s to （15.24±10.08） s （P＜0.05）. The time for drug return was reduced from 129.90 （122.32， 137.00） s to 104.36 （89.91， 117.33） s（P＜0.05）； the number of drug dispensing errors decreased from 2 cases to 0 cases. After the system was launched， there were no data security incidents in our outpatient pharmacy. CONCLUSIONS The constructed closed-loop management system for the whole-process traceability of outpatient drugs can significantly enhance drug traceability accuracy and drug management quality， improve pharmacist work efficiency， and reduce drug management risks， thus providing a feasible solution for the digital transformation of hospital pharmaceutical services.

OBJECTIVE: To compare clinical effect of arthroscopic double row fixation and single row fixation in treating Ideberg typeⅠA scapular glenoid fracture. METHODS: From June 2018 to December 2022, 26 patients with Ideberg typeⅠA scapular glenoid fracture treated with shoulder arthroscopy were divided into single-row anchor group and double-row anchor group according to the fixation method of fracture block. There were 12 patients in single-row anchor group, including 7 males and 5 females, aged from 25 to 53 years old with an average of (38.42±9.61) years old;the time from injury to operation ranged from 2 to 7 days with an average of (4.75±1.82) days. There were 14 patients in double-row anchor group, including 10 males and 4 females, aged from 21to 53 years old with an average of (37.36±10.19) years old;the time from injury to operation ranged from 1 to 8 days with an average of (4.21±2.01) days. The changes of shoulder joint flexion, abduction, lateral lateral rotation, Constant-Murley shoulder function score and Rowe scores were compared between two groups before operation and 1 year after operation. The percentage of bone mass in pelvis area before operation and the percentage of bone defect in pelvis area at the latest follow-up were compared between two groups. RESULTS: All patients were followed up for 12 to 15 months with an average of (13.08±1.17) months in single-row anchor group and 12 to 15 months with an average of (13.29±1.07) months in double-row anchor group, with no statistical significance between two groups (P>0.05). The results of anterior flexion, abduction and lateral lateral rotation in single-row anchor group were(86.67±6.62) °, (79.50±5.68) °, (38.17±1.70) ° before operation, and (162.50±4.52)°, (169.17±3.35)°, (50.67±10.20)° at 1 year after operation; while in double-row anchor group were (84.14±5.48) °, (81.71±5.20) °, (39.29±3.63) ° before operation and (162.29 ± 5.53) °, (167.14±3.61) °, (56.93±9.56) ° at 1 year after operation;the difference between two groups before operation and 1 year after operation was statistically significant (P<0.05). There were no significant difference between two groups (P>0.05). Constant-Murley scores and Rowe scores in single-row anchor group were (55.42±3.75), (43.75±18.49) before operation and (94.83±2.21), (95.42±4.50) at 1 year after operation, respectively;while in double-row anchor group were (54.50±7.88), (41.79±18.25) before operation and (94.36±4.73), (95.00±4.80) at 1 year after operation;there was no significant difference in Constant-Murley score and Rowe score between two groups before operation and 1 year after operation (P>0.05). There was significant difference in the percentage of bone mass in pelvis area between two groups before operation (P>0.05). There was no significant difference in the percentage of bone defect in the shoulder area between single-row anchor group(4.42±1.51)% and double-row anchor group (2.71±1.44)% at 1 year after operation (P<0.05). CONCLUSION Both single and double row fixation techniques for the treatment of Ideberg typeⅠA scapular glenoid fracture could receive satisfactory functional recovery. However, double-row fixation has more advantages in reducing bone resorption of fracture mass.
Humans ; Female ; Male ; Middle Aged ; Arthroscopy/methods* ; Adult ; Scapula/surgery* ; Case-Control Studies ; Fractures, Bone/physiopathology* ; Fracture Fixation, Internal/methods* ; Shoulder Joint/physiopathology* ; Range of Motion, Articular

OBJECTIVE: To explore clinical efficacy of autologous platelet-rich plasma(PRP) in treating Rockwood type Ⅲ acromioclavicular dislocation. METHODS: From January 2019 to July 2021, 32 patients with Rockwood type Ⅲ acromioclavicular dislocation were treated with minimally invasive adjustable titanium plate internal fixation, and were divided into PRP group and control group according to whether PRP treatment was performed, with 16 patients in each group. In PRP group, there were 10 males and 6 females, aged from 28 to 47 years old with an average of (36.75±7.14) years old;the time from injury to surgery ranged from 1 to 31 h with an average of (26.13±3.98) h;5 patients on the left side and 11 patients on the right side;PRP was injected once during operation and the 4th and 8th weeks after operation respectively. In control group, there were 8 males and 8 females, aged from 30 to 52 years old with an average of (38.50±5.48) years old; the time from injury to surgery ranged from 1 to 29 h with an average of (25.48±3.11) h;7 patients on the left side and 9 patients on the right side; minimally invasive surgical treatment was performed. Visual analogue scale(VAS) was used to evaluate pain and Constant-Murley score for shoulder joint function was used to evaluate the recovery of shoulder joint movement function before operation and 1, 3, 6, and 12 months after operation respectively. RESULTS: All patients were followed up for 12 to 28 months with an average of (18.3±5.2) months. All incisions patients healed well without adverse events such as infection. Postoperative VAS of PRP group at 1, 3, and 6 months were (5.5±1.2), (3.7±1.6), and (2.4±1.2), respectively, while were lower than those of control group (6.6±1.4), (4.9±1.1), and (3.7±1.3), respectively;and had statistical differences between two groups (P<0.05). There was no statistically significant difference in VAS between two groups before operation and 12 months after operation (P>0.05). Postoperative Constant-Murley scores of PRP group at 1, 3, and 6 months were (64.09±11.61), (73.19±12.89), and (82.61±14.81) points, respectively, which were higher than those of control group were (52.32±17.42), (61.65±14.43), and (72.52±11.04) respectively;and the differences were statistically significant (P<0.05). There was no statistically significant difference in Constant-Murley scores at 12 months after operation between two groups (P>0.05). In PRP group, there was no statistically significant difference at 6 months and 12 months after operation (P>0.05), while there were statistically significant differences at the other time points (1 month after operation compared with before operation, 3 months after operation compared with 6 months after operation, and 3 months after operation compared with 1 month after operation) (P<0.05). In control group, there was no statistically significant difference when comparing 1 month and 3 months after operation (P>0.05), while at the other time points (1 month after operation with before operation, 3 months after operation with 6 months after operation, and 6 months after operation with 12 months after operation), the differences were all statistically significant (P<0.05). CONCLUSION Adjustable titanium plate fixation combined with postoperative injection of PRP for the treatment of Rockwood type III acromioclavicular joint dislocation has effect of promoting the recovery of shoulder joint function and reducing pain.
Humans ; Male ; Female ; Adult ; Middle Aged ; Platelet-Rich Plasma ; Acromioclavicular Joint/surgery* ; Bone Plates ; Titanium ; Joint Dislocations/therapy* ; Fracture Fixation, Internal/methods*

Taxifolin (TAX) is a natural compound known for its liver protection effect, but the mechanism remains unknown. Phosphorylated proteomics analyses discovered that the phosphorylation level of NDRG1 at T328 was a key event of TAX-improved liver fibrosis. We established models with NDRG1 knockout (KO) in vivo and in vitro, demonstrating that NDRG1 KO attenuated the development of hepatocyte injury, and combining NDRG1 KO and TAX administration did not result in a reduction in protection against liver injury. Cellular thermal shift assay and surface plasma resonance analysis showed that TAX directly binds to NDRG1 rather than its upstream kinase, subsequently demonstrating that TAX regulated phosphorylation of NDRG1 at T328 through binding to its C289 site. NDRG1 T328A (phosphorylated mutation) and T328E (mimic phosphorylation) in vivo and in vitro confirmed that pNDRG1_T328 exacerbates hepatocyte injury along with DNA damage, inflammatory response, and apoptosis, thereby contributing to hepatic stellate cells (HSCs) activation. In contrast, TAX can inhibit the above pathological abnormalities and block hepatocyte injury-triggered HSCs activation and fibrosis. Overall, TAX is a potent liver protection drug primarily targeting NDRG1 and inhibiting pNDRG1_T328 in hepatocytes.

Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

OBJECTIVES: To explore the mechanism by which Pulsatilla saponin D (PSD) inhibits invasion and metastasis of triple-negative breast cancer (TNBC). METHODS: The public databases were used to identify the potential targets of PSD and the invasion and metastasis targets of TNBC to obtain the intersection targets between PSD and TNBC. The "PSD-target-disease" interaction network was constructed and protein-protein interaction (PPI) analysis was performed to obtain the core targets, which were analyzed for KEGG pathway and GO functional enrichment. Molecular docking study of the core targets and PSD was performed, and the therapeutic effect and mechanism of PSD were verified using Transwell assay and Western blotting in cultured TNBC cells. RESULTS: Network pharmacology analysis identified a total of 285 potential PSD targets and 26 drug-disease intersection core targets. GO analysis yielded 175 entries related to the binding of biomolecules (protein, DNA and RNA), enzyme activities, and regulation of gene transcription. KEGG analysis yielded 46 entries involving pathways in cancer, chemical carcinogenesis-receptor activation, microRNAs in cancer, chemical carcinogenesis-reactive oxygen species, PD-L1 expression and PD-1 checkpoint pathway in cancer. Molecular docking showed high binding affinities of PSD to MTOR, HDAC2, ABL1, CDK1, TLR4, TERT, PIK3R1, NFE2L2 and PTPN1. In cultured TNBC cells, treatment with PSD significantly inhibited cell invasion and migration and lowered the expressions of MMP2, MMP9, N-cadherin and the core proteins p-mTOR, ABL1, TERT, PTPN1, HDAC2, PIK3R1, CDK1, TLR4 as well as NFE2L2 expressionin the cell nuclei. CONCLUSIONS The inhibitory effects of PSD on TNBC invasion and metastasis are mediated by multiple targets and pathways.
Humans ; Triple Negative Breast Neoplasms/metabolism* ; Saponins/pharmacology* ; Pulsatilla/chemistry* ; Female ; Molecular Docking Simulation ; Cell Line, Tumor ; Neoplasm Invasiveness ; Protein Interaction Maps ; Neoplasm Metastasis ; Signal Transduction/drug effects* ; Cell Movement/drug effects*