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.

ObjectiveNon-invasive magnetic stimulation technology has been widely used in the treatment of Alzheimer’s disease (AD), but there is a lack of convenient and timely methods for evaluating and providing feedback on the effectiveness of the stimulation, which can be used to guide the adjustment of the stimulation protocol. This study aims to explore the possibility of heart rate variability (HRV) in diagnosing AD and guiding AD magnetic stimulation intervention techniques. MethodsIn this study, we used a 40 Hz, 10 mT pulsed magnetic field to expose AD mouse models to whole-body exposure for 18 d, and detected the behavioral and electroencephalographic signals before and after exposure, as well as the instant electrocardiographic signals after exposure every day. ResultsUsing one-way ANOVA and Pearson correlation coefficient analysis, we found that some HRV indicators could identify AD mouse models as accurately as behavioral and electroencephalogram(EEG) changes (P<0.05) and significantly distinguish the severity of the disease (P<0.05), including rMSSD, pNN6, LF/HF, SD1/SD2, and entropy arrangement. These HRV indicators showed good correlation and statistical significance with behavioral and EEG changes (r>0.3, P<0.05); HRV indicators were significantly modulated by the magnetic field exposure before and after the exposure, both of which were observed in the continuous changes of electrocardiogram (ECG) (P<0.05), and the trend of the stimulation effect was more accurately observed in the continuous changes of ECG. ConclusionHRV can accurately reflect the pathophysiological changes and disease degree, quickly evaluate the effect of magnetic stimulation, and has the potential to guide the pattern of magnetic exposure, providing a new idea for the study of personalized electromagnetic neuroregulation technology for brain diseases.

BACKGROUND: There is little literature describing the artificial intelligence (AI)-aided diagnosis of severe pneumonia (SP) subphenotypes and the association of the subphenotypes with the ventilatory treatment efficacy. The aim of our study is to illustrate whether clinical and biological heterogeneity, such as ventilation and gas-exchange, exists among patients with SP using chest computed tomography (CT)-based AI-aided latent class analysis (LCA). METHODS: This retrospective study included 413 patients hospitalized at Xinhua Hospital diagnosed with SP from June 1, 2015 to May 30, 2020. AI quantification results of chest CT and their combination with additional clinical variables were used to develop LCA models in an SP population. The optimal subphenotypes were determined though evaluating statistical indicators of all the LCA models, and clinical implications of them such as guiding ventilation strategies were further explored by statistical methods. RESULTS: The two-class LCA model based on AI quantification results of chest CT can describe the biological characteristics of the SP population well and hence yielded the two clinical subphenotypes. Patients with subphenotype-1 had milder infections ( P <0.001) than patients with subphenotype-2 and had lower 30-day ( P <0.001) and 90-day ( P <0.001) mortality, and lower in-hospital ( P = 0.001) and 2-year ( P <0.001) mortality. Patients with subphenotype-1 showed a better match between the percentage of non-infected lung volume (used to quantify ventilation) and oxygen saturation (used to reflect gas exchange), compared with patients with subphenotype-2. There were significant differences in the matching degree of lung ventilation and gas exchange between the two subphenotypes ( P <0.001). Compared with patients with subphenotype-2, those with subphenotype-1 showed a relatively better match between CT-based AI metrics of the non-infected region and oxygenation, and their clinical outcomes were effectively improved after receiving invasive ventilation treatment. CONCLUSIONS A two-class LCA model based on AI quantification results of chest CT in the SP population particularly revealed clinical heterogeneity of lung function. Identifying the degree of match between ventilation and gas-exchange may help guide decisions about assisted ventilation.
Humans ; Tomography, X-Ray Computed/methods* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Artificial Intelligence ; Aged ; Pneumonia/diagnosis* ; Latent Class Analysis ; Adult

This study aims to explore whether Naoxintong Capsules improve multiple cerebral infarctions and myocardial injury via promoting angiogenesis, thereby exerting a simultaneous treatment effect on both the brain and heart. Male SD rats were randomly divided into six groups: sham-operated group, model group, high-dose, medium-dose, and low-dose groups of Naoxintong Capsules(440, 220, and 110 mg·kg~(-1)), and nimodipine group(10.8 mg·kg~(-1)). Rat models of multiple cerebral infarctions were established by injecting autologous thrombus, and samples were collected and tested seven days after modeling. Evaluations included multiple cerebral infarction model assessments, neurological function scores, grip strength tests, and rotarod tests, so as to evaluate neuromotor functions. Morphological structures of brain and heart tissue were observed using hematoxylin-eosin(HE) staining, Nissl staining, and Masson staining. Network pharmacology was employed to screen the mechanisms of Naoxintong Capsules in improving multiple cerebral infarctions and myocardial injury. Neuronal and myocardial cell ultrastructures were observed using transmission electron microscopy. Apoptosis rate in brain neuronal cells was detected by TdT-mediated dUTP nick end labeling(TUNEL) staining, and reactive oxygen species(ROS) levels in myocardial cells were measured. Immunofluorescence was used to detect the expression of platelet endothelial cell adhesion molecule-1(CD31), antigen identified by monoclonal antibody Ki67(Ki67), hematopoietic progenitor cell antigen CD34(CD34), and hypoxia inducible factor-1α(HIF-1α) in brain and myocardial tissue. Western blot, and real-time quantitative polymerase chain reaction(RT-qPCR) were used to detect the expression of HIF-1α, vascular endothelial growth factor(VEGF), vascular endothelial growth factor receptor 2(VEGFR2), sarcoma(Src), basic fibroblast growth factor(bFGF), angiopoietin-1(Ang-1), and TEK receptor tyrosine kinase(Tie-2). Compared with the model group, the medium-dose group of Naoxintong Capsules showed significantly lower neurological function scores, increased grip strength, and prolonged time on the rotarod. Pathological damage in brain and heart tissue was reduced, with increased and more orderly arranged mitochondria in neurons and cardiomyocytes. Apoptosis in brain neuronal cells was decreased, and ROS levels in cardiomyocytes were reduced. The microvascular density and endothelial cells of new blood vessels in brain and heart tissue increased, with increased overlapping regions of CD31 and Ki67 expression. The relative protein and mRNA expression levels of HIF-1α, VEGF, VEGFR2, Src, Ang-1, Tie-2, and bFGF were elevated in brain tissue and myocardial tissue. Naoxintong Capsules may improve multiple cerebral infarctions and myocardial injury by mediating HIF-1α/VEGF expression to promote angiogenesis.
Animals ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Rats ; Cerebral Infarction/genetics* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Vascular Endothelial Growth Factor A/genetics* ; Capsules ; Signal Transduction/drug effects* ; Humans ; Brain/metabolism* ; Myocardium/metabolism* ; Apoptosis/drug effects*

OBJECTIVE: To analyze the MYH9 gene sequence of a patient with hereditary thrombocytopenia and diffuse large B-cell lymphoma and his family members, and to explore the relationship between MYH9 gene and tumors. METHODS: Peripheral blood samples were collected from the patients and their family members for complete blood count analysis. The platelet morphology was observed under microscope. The MYH9 gene sequence was analyzed by Whole Exon Sequencing and Sanger Sequencing. RESULTS: The mutation site c.279C>A:p.(Asn93Lys) in exon 2 of the MYH9 gene were found in patient and his family members, both presenting as thrombocytopenia. The platelet count was significantly increased after the administration of Avatrombopag. CONCLUSION A novel mutation of MYH9 was found in this study, and the case was sensitive to Avatrombopag, by exploring the relationship between the MYH9 gene and tumors, suggesting that the MYH9 gene may be associated with the development of diffuse large B-cell lymphoma.
Humans ; Myosin Heavy Chains/genetics* ; Thrombocytopenia/genetics* ; Mutation ; Male ; Lymphoma, Non-Hodgkin/genetics* ; Lymphoma, Large B-Cell, Diffuse/genetics* ; Molecular Motor Proteins/genetics* ; Pedigree

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

To investigate the role of chamagogic polysaccharides (polysaccharides of Brassica rapa L., BRPs) against doxorubicin (DOX) cardiotoxicity and related mechanisms, H9c2 cells were selected for the study, and the effects of BRPs on DOX induced damage in H9c2 cells were detected by cell counting kit-8 (CCK-8); H9c2 cells were divided into the control group, the model group, and the drug group (0.5-3 mg·mL^-1); the control group was cultured under normal conditions, and the remaining groups were induced for 24 h by 1 μmol·L^-1 DOX after treatment. Apoptosis was detected by flow cytometry; the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured in each group; intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected. Western blot was used to detect the expression of proteins related to the apoptosis and transcription factor NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Compared with the control group, DOX-induced H9c2 cell injury was characterized by decreased cell viability, increased apoptosis, elevated LDH and MDA levels, decreased SOD activity, significantly increased ROS levels, and significantly decreased MMP; the level of B cell lymphoma-2 (Bcl-2) protein decreased, and the level of Bcl-2 associated X protein (Bax) increased significantly; In the model group, the expression levels of Nrf-2, HO-1, quinone oxidoreductase 1 (NQO1) were reduced, and the expression levels of Kelch-like ECH-associated protein 1 (Keap1) and phosphorylated p38 mitogen-activated protein kinase were significantly increased, Moreover, BRPs (0.5-3 mg·mL^-1) increased the protein expression levels of Nrf2, HO-1, and NQO1, and decreased the levels of Keap1 and phosphorylated p38 mitogen-activated protein kinase. In summary, the ability of BRPs to protect H9c2 cells and inhibit apoptosis may be related to their regulation of the Nrf2/HO-1 pathway to antagonize oxidative stress.

Aim To study the effect of salidroside combined with rosavin on ischemic stroke in rats.Methods The model of MCAO was established by u-sing thread-embolic method.The rats were divided into the sham group,MCAO group,salidroside combined with rosavin group,positive control group,and the drug was given continuously for seven days.The infarct volume was measured by MRI and neurological deficit score was evaluated by Zea-Longa.The levels of Ne-uN,BDNF,TGF-β1,p-Smad were observed by West-ern blot and immunofluorescence staining.The expres-sions of IL-1β,TNF-α and IL-6 were performed by RT-qPCR/ELISA.The primary cortical neurons were isolated,OGD/R inducted,divided into the normal group,OGD/R group,salidroside combined with rosa-vin group,and TGF-β1 inhibitor+salidroside com-bined with rosavin group,the drug was given for 24 hours,and the expressions of NeuN,BDNF,IL-1β,TNF-α and IL-6 were measured.Results Salidroside combined with rosavin could decrease the infarct vol-ume,improve the neurological function,promote the levels of Neun,BDNF,TGF-β1,p-Smad,and inhibit the expressions of IL-1β,TNF-α and IL-6.Salidroside combined with rosavin could promote NeuN,BDNF,inhibit IL-1β,TNF-α,IL-6 in primary nerve cells in-duced by OGD/R,and these effects were blocked by TGF-β1 inhibitor.Conclusions Salidroside combined with rosavin has neuroprotective effects on MCAO rats,and primary neurons are induced by OGD/R,and these effects are closely related to the TGF-β pathway.

Objective:To investigate the correlation between serum albumin, urea nitrogen and Fazekas scores and cognitive function scores in patients with mild and medium ischemic stroke.Methods:Clinical data of 160 patients with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS)≤7 scores admitted to the Department of Neurology of the First Affiliated Hospital of Hainan Medical College from June 2021 to April 2023 were selected for a cross-sectional study. According to the Montreal Cognitive Assessment (MoCA) score, they were divided into normal cognitive group (28 cases) (MoCA≥26 scores), mild to moderate cognitive impairment group (74 cases) (MoCA 15-<26 scores), and severe cognitive impairment group (58 cases) (MoCA<15 scores). Demographic characteristics, serological indicators and imaging data of patients were collected, and the correlation between serum albumin, urea nitrogen and Fazekas scores and the total score of MoCA and the scores of each cognitive domain was analyzed. One-way ANOVA was used for comparison between the normal distribution and homogeneous variance data sets, LSD analysis was used for pairwise comparison, Kruskal-Wallis H test was used between the skew distribution or heterogeneous variance data sets. Bonferroni correction analysis was used for pairwise comparison. Chi-square test or Fisher exact probability method was used after the comparison between the count data sets. Spearman Spearman correlation analysis was performed on serum albumin, urea nitrogen and Fazekas scores with MoCA scores and cognitive domain scores. Multivariate ordered Logistic regression was used to analyze the independent risk factors of cognitive function in acute stage of mild and medium ischemic stroke patients. Results:The incidence of cognitive impairment in patients with acute mild and medium ischemic stroke was 82.50% (132/160). Comparison of age ((56.71±7.35), (60.32±10.20), (66.40±11.88) years old), sex (male/female: (23/5, 58/16, 33/25)), the proportion of education level above high school (25.0%(7/28), 16.2%(12/74), 6.9%(4/58)), hemoglobin ((149.26±14.91), (144.85±16.85), (137.63±17.22) g/L), albumin (39.5 (37.0, 41.2), 38.6(35.6, 40.8), 37.4 (34.5, 39.8) g/L), urea nitrogen (5.30 (4.00, 6.60), 4.81 (4.00, 6.32), 5.86 (4.55, 6.97) mmol/L), Hamilton Anxiety Scale (HAMA) score (5.0 (2.0, 10.0), 7.5 (5.0, 11.0), 10.0 (6.0, 14.3) scores),Hamilton Depression Scale (HAMA) score (5.5 (3.0, 12.5), 7.0 (4.0, 11.0), 9.5 (5.0, 14.0) scores), and Fazekas score (2.00 (1.25, 3.00), 2.00 (1.00, 4.00), 3.00 (2.00, 5.00) scores) among cognitive normal group, mild to moderate cognitive impairment group, and severe cognitive impairment group of patients, the difference were statistically significant (the statistical values were F=9.68, χ 2=9.29, χ 2=30.77, F=5.31, H=7.06, H=6.71, H=12.37, H=8.91, and H=10.96, respectively;the P values were <0.001, 0.010, <0.001, 0.006, 0.029, 0.035, 0.002, 0.012, and 0.004, respectively ). The total score of MoCA was negatively correlated with Fazekas score and serum urea nitrogen, but positively correlated with serum albumin ( r s values were -0.250, -0.168, and 0.212, respectively; P values were 0.001, 0.036, and 0.009, respectively). Serum albumin was positively correlated with scores in visual space and execution, naming, attention and orientation, serum urea nitrogen was negatively correlated with scores in language and orientation, and Fazekas score was negatively correlated with scores in visual space and execution, orientation, attention and language ( r s values were 0.291, 0.196, 0.191, 0.209, -0.205, -0.180, -0.248, -0.193, -0.188, and -0.183, respectively; P values were <0.001, 0.017, 0.020, 0.011, 0.012, 0.027, 0.002, 0.016, 0.020, and 0.023, respectively). Multiple Logistic regression analysis showed that low albumin ( OR=0.884, 95% CI: 0.813-0.963, P=0.005) and high urea nitrogen ( OR=1.195, 95% CI: 1.003-1.425, P=0.047) and high Fazekas scores ( OR=1.401, 95% CI: 1.132-1.733, P=0.002) were independent risk factors for cognitive function, while high education level was a protective factor ( OR=0.062, 95% CI: 0.019-0.202, P<0.001). Conclusion:The incidence of acute cognitive impairment is high in patients with mild and medium ischemic stroke. Higher education level is a protective factor for cognitive function. Low albumin, high urea nitrogen and high Fazekas score are independent risk factors for cognitive function.

Objective:To develop and validate a model to predict the risk of malnutrition in patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy. Methods:From April 2022 to August 2023, 430 patients with nasopharyngeal carcinoma who were admitted to the department of radiotherapy of the first affiliated hospital of Guangxi medical university in Nanning were conveniently selected as the study subjects, and they were divided into the modelling group (300 cases) and the internal validation group (130 cases) in the internal validation group in the ratio of 7:3, and 61 patients with nasopharyngeal carcinoma admitted to the affiliated cancer hospital of Guangxi medical university in Nanning City were selected as the external validation group. Logistic regression was used to establish the risk prediction model and draw nomograms,Hosmer-Lemeshow, calibration curve and ROC were used to verify the goodness of fit and predictive power of the model, and clinical decision curve was used to assess the clinical utility. Results:Logistic regression analysis showed that skeletal muscle mass index, self-rated anxiety scale score, Pittsburgh sleep quality questionnaire score, Chinese diet pagoda score, regular exercise, and digestive symptom groups were the influencing factors for malnutrition in patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy. In the modelling group, the area under the ROC curve was 0.853 (95％CI:0.81 ～ 0.89), the maximum Youden was 0.600, and the corresponding specificity was 0.764 and the sensitivity was 0.836. The Hosmer-Lemeshow test=4.040 and P=0.853 indicated that the model had good predictive ability. Calibration curve of the calibration showed that the predictive effect of the model matched actual probability well, with an average absolute error was 0.024. When the threshold probability of the clinical decision curve is 0.05 ～ 0.85, the clinical response rate is higher. The area under the operating curve of the subjects in the internal validation group was 0.891, the sensitivity was 77.36％, the specificity was 89.61％, and the practical application accuracy was 84.62％. The area under the operating curve of the subjects in the external validation group was 0.886, the sensitivity was 76.00％, the specificity was 83.33％, and the overall accuracy was 80.33％. Conclusion:The risk prediction model constructed in this study has a good effect, which can effectively predict the incidence of malnutrition in patients receiving concurrent radiotherapy and chemotherapy for nasopharyngeal carcinoma, and provide a reference for clinical staff to formulate and implement nutritional interventions.