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.

Objective To analyze three-dimensional imaging characteristics and advantages for severe portal vein stenosis after liver transplantation, and to evaluate clinical efficacy of portal vein stent implantation. Methods Clinical data of 10 patients who received portal vein stent implantation for severe portal vein stenosis after liver transplantation were retrospectively analyzed. Imaging characteristics of severe portal vein stenosis, and advantages of three-dimensional reconstruction imaging and interventional treatment efficacy for severe portal vein stenosis were analyzed. Results Among 10 patients, 3 cases were diagnosed with centripetal stenosis, tortuosity angulation-induced stenosis in 2 cases, compression-induced stenosis in 2 cases, long-segment stenosis and/or vascular occlusion in 3 cases. Three-dimensional reconstruction images possessed advantages in accurate identification of stenosis, identification of stenosis types and measurement of stenosis length. All patients were successfully implanted with portal vein stents. After stent implantation, the diameter of the minimum diameter of portal vein was increased [(6.2±0.9) mm vs. (2.6±1.7) mm, P<0.05], the flow velocity at anastomotic site was decreased [(57±19) cm/s vs. (128±27) cm/s, P<0.05], and the flow velocity at the portal vein adjacent to the liver was increased [(41±6) cm/s vs. (18±6) cm/s, P<0.05]. One patient suffered from intrahepatic hematoma caused by interventional puncture, which was mitigated after conservative observation and treatment. The remaining patients did not experience relevant complications. Conclusions Three-dimensional visualization technique may visually display the location, characteristics and severity of stenosis, which is beneficial for clinicians to make treatment decisions and assist interventional procedures. Timely implantation of portal vein stent may effectively reverse pathological process and improve portal vein blood flow.

This paper explains the mechanism of the mutual switching between physiological sleep and wakefulness from the aspects of the sleep circadian system and the sleep homeostasis system. In the circadian rhythm system, with the suprachiasmatic nucleus as the core, the anatomical connections between the suprachiasmatic nucleusand various systems that affect sleep are summarized, starting from the suprachiasmatic nucleus, passing through the four pathways of the melatonin system, namely, subventricular area of the hypothalamus, the ventrolateral nucleus of the preoptic area, orexin neurons, and melatonin, then the related mechanisms of their regulation of sleep and wakefulness are expounded. In the sleep homeostasis system, with adenosine and prostaglandin D2 as targets, the role of hypnogen in sleep arousal mechanisms in regulation is also expounded.

Objective To establish a method for testing isolated mitral valve in vitro and quantitatively evaluate the effect of transcatheter edge-to-edge repair technology(TEER)on functional mitral regurgitation(FMR)(non-A2-P2 regurgitation).Methods In this study,an FMR(non-A2-P2 regurgitation)model was developed by dilating the annulus orifice and displacing the papillary muscle in isolated porcine mitral valve.The hydrodynamics characteristics of 6 valves were tested by a pulsatile flow testing system under different physiological and pathological conditions before and after TEER.Results The results show that the valve regurgitation improved from moderate-severe[regurgitant fraction(60.2±17.5)％]to mild-moderate[regurgitant fraction(34.7±12.0)％]by repair(P＜0.001).The EOA[(3.8±1.6)cm2 vs.(2.2±0.5)cm2,P＜0.001]and the forward cross valve pressure difference[(1.8±1.3)mmHg vs.(3.8± 1.8)mmHg,P＜0.001],which characterize the forward flow performance of the valve,were compared before and after repair,and the differences were statistically significant.At the same time,the repair caused valve stenosis(the effective orifice area decreased by 40％and the positive differential pressure increased by 110％),but the valves was still within the normal physiological range,and no iatrogenic stenosis was caused.Conclusions It can be seen that TEER has an effect on FMR.This study provides validation and evaluation methods in vitro for expanding indications and improving TEER,and reference for developing standards of transcatheter valve repair testing in vitro.

Objective To investigate the mechanism of Gentianopsis paludosa xanthone(GPX)combined with probiotics in the intervention of colon inflammation-tumor transformation in rats by regulating TGF-β1/Smads pathway and inflammatory factors.Methods Ninety rats were divided into the normal group,the model group[drinking sodium dextran sulfate(DSS)for 3 days]and the intervention group by random number table method.The model group was subdivided into the inflammatory stage group,the pre-inflammatory cancer group(DMH injection for 4 weeks),the intermediate inflammatory cancer group(DMH injection for 13 weeks)and the advanced inflammatory cancer group(DMH injection for 21 weeks).The administration group was subdivided into the groups(after the first day of drinking DSS,drugs for each group were given by gavage once a day for 8 weeks)on the basis of the advanced inflammatory cancer group,including the GPX group(GPX 69.3 mg/kg),the probiotic group,the combined group(GPX+probiotics 400 mg/kg)and the thalidomide group(thalidomide 13.5 mg/kg).The disease activity index(DAI),colon length and wet mass index were compared between all groups.Characteristics of colon tumors were observed,and pathological changes of colon were observed by HE staining.The expression levels of transforming growth factor(TGF)-β1,Smad4,Smad7,interleukin(IL)-6 and tumor necrosis factor(TNF)-α were detected by Western blot assay and enzyme-linked immunosorbent assay,respectively.Results Compared with the advanced inflammatory cancer group,the administration groups showed an increase in colon length,the expression levels of TGF-β1 and Smad4 protein,a decrease in colon wall thickness,wet mass index,maximum tumor diameter,the levels of Smad7,IL-6,TNF-α,and DAI score decreased in the GPX group and the combined group(P＜0.05).The structure and morphology of intestinal mucosa were improved in the GPX group,the probiotic group and the combination group,and the structure of colonic crypt and goblet cell number were increased.Compared with the probiotic group and the GPX group,the colon wall thickness,colon wet mass index and tumor number were decreased,the protein expression levels of TGF-β1 and Smad4 were increased,and levels of IL-6 and TNF-α were decreased in the combination group(P＜0.05).Conclusion GPX combined with probiotics could inhibit the transformation of colon inflammation-tumor,and the mechanism may be related to the regulation of TGF-β1/Smads pathway and the inhibition of pro-inflammatory factors of IL-6 and TNF-α.

AIM:To explore the molecular mechanism of Tiaopi Chengqi decoction (TpCqD) improving hyperthermia and high-protein food-induced hyperphagia mice based on transcriptomics. METHODS:C57 mice were randomly divided into a control group, model group, low-dose TpCqD group, high-dose TpCqD group, and domperidone group. The general condition of the experimental mice was observed and the average food intake was counted, and the rate of gastric emptying and intestinal propulsion was determined for each group of mice. H&E staining was used to observe pathological changes in gastric tissue. PAS staining was used to observe glycogen changes in gastric tissue. Pepsin activity was determined by colorimetry. pH value of gastric contents was measured by acid-base titration. Transcriptome sequencing was used to analyze the differential genes in gastric tissue, a volcano map and a cluster heat map were made for the differential genes, and KEGG was used to analyze the signal pathway enrichment of the differential genes. RT-qPCR verified the differential genes obtained by screening. RESULTS:After treatment with TpCqD, the body weight and average food intake of mice with food accumulation increased (P<0.05), and the intestinal propulsion rate and gastric emptying speed of mice with food accumulation accelerated (P<0.05). TpCqD could protect gastric tissue structure and glycogen degradation, increase pepsin activity (P<0.05), and reduce gastric content pH (P<0.05). Transcriptome results showed that TpCqD could regulate the expression of Acox2 and cilp2, regulate fat digestion and absorption, protein digestion and absorption, and pancreatic secretion signals. RT-qPCR showed that compare with model group, TpCqD up-regulated Acox2 (P<0.05) and down-regulated the mRNA level of cilp2 (P<0.05). CONCLUSION:TpCqD ameliorated digestive dysfunction in mice with high-calorie and high-protein diets leading to food accumulation involving the regulation of the fat and sugar metabolism genes Acox2 and cilp2, and pancreatic secretory signaling.

Objective:To analyze the seroepidemiological characteristics of hepatitis B virus (HBV) infection among adolescents aged 0-14 years in Henan Province and to evaluate the effectiveness of the childhood hepatitis B vaccine (HepB) immunization program.Methods:From September 2021 to March 2022, a total of 4 883 adolescents aged 0-14 years were selected from 25 villages or communities of 18 provincial-level cities in Henan Province by using the multi-stage random cluster sampling method. Demographic data were collected through questionnaires. The 3 ml of blood samples were collected from individuals aged 0-4 years and 5 ml of blood samples were collected from individuals aged 5-14 years to test HBsAg, HBcAb and HBsAb. Data on vaccination were collected through Henan Provincial Immunization Information System and hepatitis B cases in Henan Province were collected through China Infectious Disease Reporting System. The effectiveness of the childhood HepB immunization program was analyzed.Results:The average age of 4 883 subjects was (7.32±2.81) years old. The positive rates of HBsAg and HBcAb were 0.1% (7/4 883) and 1.0% (50/4 883), and the population standardized rates were 0.3% and 1.7%. In 2002, the positive rate of HBsAg among adolescents aged 0-14 years in Henan Province was 3.39%. Compared with that in 2002, the number of chronic HBV infections among adolescents in Henan Province in 2022 decreased by about 0.7 million. In 2002, the vaccination rate of newborns who completed all three doses of vaccine was 6.26%. In 2003, the vaccination rate of the hepatitis B vaccine rose rapidly, reaching 90% in 2013 for the first time. After 2014, the vaccination rate in Henan Province continued to remain above 95%. The proportion of cases among children aged 1-4 years in clinical reports decreased from 0.43% (1 108/256 566) in 2006 to 0.01% (78/80 655) in 2021. The proportion of cases among adolescents aged 5-19 years decreased from 18.21% (46 710/256 566) in 2006 to 1.1% (827/80 655) in 2021.Conclusions:From 2002 to 2022, the positive rate of HBsAg among adolescents aged 0-14 years has decreased significantly in Henan Province. The effectiveness of the HepB immunization program for children is good.

ObjectiveTo employ the effective components and antiarrhythmic mechanism of Wenxin Granules （WXKL） by cell membrane chromatography （CMC） and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF/MS）， combined with network pharmacology. MethodIn this study， the CMC/UPLC-Q-TOF/MS technique was employed to identify the components in WXKL that could specifically bind to myocardial cell membranes. By utilizing databases such as SwissTarget Prediction and GeneCards， the targets of WXKL's effective components and arrhythmia-related targets were mined. Cytoscape software was used to construct a "component-target-disease" network. Gene ontology（GO） function and Kyoto encyclopedia of genes and genomes（KEGG） pathway enrichment analyses were carried out， and molecular docking of key components and targets was performed. Finally， further verification was conducted through in vivo experiment of rats. ResultA total of 39 effective components were identified in WXKL. These included 13 components derived from Panax notoginseng， 15 components from Codonopsis pilosula， seven components from Glycyrrhizae Radix et Rhizoma， one component from Succinum， one component from Polygonatum odoratum， one component shared by both P. odoratum and C. pilosula， and one component shared by both Panax notoginseng and C. pilosula. Network pharmacology predicted that WXKL had 16 core antiarrhythmic targets and 79 related pathways， mainly involving adrenergic signaling in cardiomyocytes， cyclic guanosine monophosphate （cGMP）/protein kinase G （PKG）， calcium signal， cyclic adenosine monophosphate （cAMP）， interleukin （IL）-17， mitogen-activated protein kinase （MAPK）， and tumor necrosis factor （TNF） signaling pathways. The results of in vivo experiment of rats showed that WXKL significantly improved the expression of β₁-adrenergic receptor （β₁-AR）， cAMP， TNF-α， and calcium voltage-gated channel subunit alpha 1C （CACNA1C）. ConclusionWXKL can exert its antiarrhythmic effects through multiple components， multiple targets， and multiple pathways. This study provides a scientific basis for explaining the potential pharmacodynamic substance foundation and mechanism of action of traditional Chinese medicine in treating arrhythmia.

Objective To analyze the clinical outcomes of extended thymectomy for myasthenia gravis (MG) patients under different surgical approaches, and to determine the factors affecting the prognosis of MG. Methods The MG patients who underwent extended thymectomy from January 2014 to March 2021 in our hospital were retrospectively collected. According to the surgical approach, they were divided into a subxiphoid group and an intercostal group, and the perioperative results and prognosis were compared between the two groups. A “good outcome” was defined as complete stable remission (CSR), pharmacological remission (PR) or minimal manifestations state (MMS); a “poor outcome” was defined as outcomes worse than MMS. Univariate and multivariate logistic regression analyses were performed to assess the factors associated with the good outcomes. Results A total of 187 MG patients were included in the study, including 82 males and 105 females, with a median age of 50 (36, 60) years. There were 134 patients in the intercostal group and 53 patients in the subxiphoid group. Compared with the intercostal group, although the operation time of the subxiphoid group was longer [200.0 (172.0, 232.0) min vs. 141.0 (118.0, 169.0) min, P<0.001], the intraoperative blood loss was less [10.0 (10.0, 20.0) mL vs. 20.0 (10.0, 50.0) mL, P<0.001], the postoperative hospital stay was shorter [3.0 (2.5, 4.0) d vs. 5.0 (3.0, 7.0) d, P<0.001], and the incidence of complications was lower [1 (1.9%) vs. 26 (19.4%), P=0.001]. A total of 159 (85.0%) patients were followed up for a median period of 46 (13, 99) months, with a good outcome rate of 90.6% and CSR rate of 33.3%. There were no statistical differences in PR, MMS or overall good outcome rates between the two groups (P>0.05). Multivariate logistic analysis showed that age≤50 years was an independent predictor for "good outcome" of MG patients. Conclusion Extended thymectomy via subxiphoid for MG is a safe, feasible and effective surgical approach.

AIM:To establish a model of meibomian gland dysfunction in rats induced by eyeliner tattoo and investigate its potential mechanisms.METHODS:A total of 40 SD rats were selected, with 30 randomly chosen to have eyeliner tattoo applied their right eyes and designated as the eyeliner group. The remaining 10 rats were not given any treatment and served as the normal group. The corneal morphology of both groups was observed using a slit lamp at 1, 2, and 4 wk after establishment, and the tear film break-up time(BUT), Schirmer I test(SIt), corneal fluorescein staining score, and corneal irregularity score were calculated. The corneal Placido rings were examined using an ocular surface analyzer, and the corneal tissue structures of both groups were observed under a confocal microscope. After 4 wk and completion of clinical indicator recording, the eyeballs and upper and lower eyelid tissues were taken for pathological examination. The meibomian gland structures were observed through HE staining, the conjunctival goblet cells were observed using PAS staining, and the lipid droplets were observed with ORO staining.RESULTS:The slit lamp examination results showed that the eyeliner group rats exhibited in situ black pigmentation in the eyelids, with no eyelid deformation or scarring. The corneal epithelium was rough, with positive fluorescein staining, presenting as spotty staining that worsened over time. Compared with the normal group, the BUT was significantly shortened, tear secretion volume was significantly decreased, and the corneal fluorescein staining score and corneal irregularity score were significantly increased at 1, 2, and 4 wk after modeling in the eyeliner group(all P<0.01). The corneal confocal microscopy results showed a decrease in corneal epithelial cells in the eyeliner group, with the appearance of abnormally bright cells, and inflammatory cell infiltration visible in the stromal layer. The ORO staining results revealed a decrease in lipid droplets in the eyeliner group, showing a downward trend with increasing observation time. The HE staining results showed that pigment blocked the meibomian gland openings in the eyeliner group, and the density of meibomian gland acini showed a downward trend over time. The PAS staining results showed a decreasing trend in the number of PAS-positive cells in the eyeliner group.CONCLUSION:Eyeliner tattoo can induce meibomian gland dysfunction, and the blockage of meibomian gland openings caused by the pigment particles used may be an important cause of meibomian gland dysfunction.