Objective To explore the biological mechanisms of isorhamnetin(ISO)inhibition of breast cancer(BC)progression and effects on paclitaxel sensitivity by in vivo and in vitro experiments.Methods The effects of ISO on MDA-MB-231 cell viability,migration,invasion and apoptosis were explored by CCK-8,scratch,Transwell invasion and apoptosis assays.ISO biological functions were analyzed and core target genes were identified by genome-wide microarrays,functional enrichment and protein-protein interactions(PPI).CYP1B1 expression characterization and prognosis in BC were assessed by quantitative Real-time polymerase chain reaction(qRT-PCR),Western blotting(WB),and Kaplan-Meier plotter database.The effects of CYP1B1 overexpression on MDA-MB-231 cell viability,migration,invasion and apoptosis were explored by CCK-8,scratch,Transwell invasion and apoptosis assays.The effects of ISO and CYP1B1 on BC tumor growth were analyzed by establishing a subcutaneous graft tumor animal model and verified by histological analysis with immunohistochemistry(IHC)and hematoxylin and eosin(HE)staining.The effects of ISO and CYP1B1 on NF-κB signaling were analyzed by qRT-PCR and WB.The effect of ISO combined with paclitaxel on BC progression was analyzed by in vitro and in vivo experiments.Results The results of CCK-8 assay showed that ISO inhibited the viability of MDA-MB-231 cells with an IC50 value of 11.93 μmol/L;the scratch,Transwell invasion and apoptosis assays confirmed that ISO inhibited the migration and invasion of MDA-MB-231 cells and promoted apoptosis(P＜0.05).Volcano plot showed a total of 80 differentially expressed genes(DEGs),of which ISO promoted the expression of 27 genes and inhibited the expression of 53 genes.Gene set enrichment analyses showed that DEGs were mainly enriched in the signaling of organic hydroxyl compound metabolic process,inflammatory response,sterol metabolic process,and nuclear factor-κB(NF-κB).qRT-PCR,WB,and Kaplan-Meier plotter results showed that CYP1B1 mRNA and protein expression was increased in BC and mediated worse prognosis(P＜0.05).CCK-8,scratch,Transwell invasion and apoptosis assays showed that CYP1B1 overexpression enhanced MDA-MB-231 cell viability,migration and invasion,and inhibited apoptosis,which was reversed by the addition of ISO(P＜0.05).The results of in vivo experiments showed that ISO downregulated CYP1B1 expression and attenuated NF-κB signaling(P＜0.05).The results of in vitro and in vivo experiments showed that ISO combined with paclitaxel significantly inhibited BC cell viability and tumor growth(P＜0.05).Conclusion ISO inhibits BC malignant biological behavior by modulating the CYP1B1/NF-κB signaling axis,and ISO enhances paclitaxel sensitivity.

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.

Objectives:Comparative analysis of the beagles acute-phase electrocardiographic,hemodynamic,left ventricular flow field status,and energy consumption characteristics of pacing at different sites of conduction system may help to elucidate the scientific mechanism of left bundle branch pacing(LBBP)as a option of physiological pacing therapy.Methods:Eight healthy adult beagles were used in this study.Initially,an active fixation lead was implanted in the right atrial appendage,followed by implantation of another active fixation lead at the right ventricular apex,distal His bundle,and left bundle septal branch,respectively.After connecting a dual-chamber pacemaker,electrocardiographic and acute phase hemodynamic parameters under sinus rhythm,right ventricular apex pacing(RVAP),distal His bundle pacing(DHBP),and LBBP states were collected and analyzed.Three complete cardiac cycles of standard apical three-chamber color Doppler dynamic images were acquired under vector flow mapping(VFM)mode.Offline analysis was performed on obtained parameters including isovolumic contraction period,rapid ejection period,isovolumic relaxation period,rapid filling period,atrial contraction period,and left ventricular intracavitary energy consumption.These parameters were compared under pacing at different sites and the linear correlations of major parameters were analyzed.Results:The QRS duration of baseline intrinsic sinus rhythm,RVAP,DHBP and LBBP were(45.0±4.0)ms,(98.4±6.2)ms,(50.0±4.5)ms and(62.0±4.7)ms,respectively.The LBBP-QRS duration was significantly wider than intrinsic sinus rhythm and DHBP,but significantly narrower than RVAP(all P<0.01).Compared with baseline AOO mode(the pacing rate was performed at 10 beats/min above the intrinsic heart rate),the change of acute phase maximum left ventricular pressure rise rate(LVdP/dtmax)in RVAP,DHBP and LBBP was([-7.89±5.67]% ),([0.74±2.05]% )and([-0.14±3.59]% ),respectively.There was no significant difference in LVdP/dtmax changes between DHBP and LBBP(P=0.667),but both pacing modalities were significantly better than RVAP(all P<0.01).The average energy consumption of the left ventricle under RVAP was significantly higher than that of intrinsic sinus rhythm,DHBP,and LBBP in isovolumic contraction period,rapid ejection period,isovolumic relaxation period,rapid filling period,and atrial contraction period(all P<0.01).However,there was no statistically significant difference in energy consumption among intrinsic sinus rhythm,DHBP,and LBBP during the above five phases(all P>0.05).DHBP and LBBP did not show a significant increase in the number of left ventricular vortices,vortex area,and circulation intensity compared to intrinsic sinus rhythm,and LBBP did not show a significant increase in vortex area and circulation intensity compared to DHBP.Conclusions:Although LBBP canines significantly prolonged the paced QRS duration,it showed no significant differences in acute phase left ventricular hemodynamics,left ventricular flow field status,and energy consumption compared to intrinsic sinus rhythm and DHBP.Performance of LBBP was superior to RVAP.This study may contribute to revealing the theoretical basis of LBBP as a feasible physiological pacing therapy.

Depression is a highly heterogeneous psychiatric disorder with complex pathogenesis influenced by the interplay of biological,psychological,and social-environmental factors.Based on the 2021 edition of the Chinese Guidelines for the Prevention and Treatment of Depressive Disorders,which explicitly identify gender as a significant risk factor for depression onset,this paper systematically reviews the gender-differentiated pathogenesis and therapeutic advances in depression from both traditional Chinese medicine(TCM)and Western medical perspectives.In Western medicine,a large number of studies have demonstrated the sex-specific mechanism of estrogen/testosterone fluctuations and monoamine transmitter system regulation.While in TCM,although the constitution theory proposes that there are significant gender differences in congenital constitution and that qi depression and qi deficiency are associated with susceptibility to depression,current evidence primarily relies on cross-sectional surveys and lacks validation through high-quality RCTs.Compared with Western medicine,the direct research on gender-differentiated antidepressant effects in TCM remains relatively underdeveloped.In future study,it may be possible to deepen and improve the research on anti-depression in TCM from the biological markers of particular constitutions in the gender dimension.This paper advocates establishing a bio-psycho-social integrated intervention model,advancing mechanistic exploration through prospective cohort studies and multi-omics technologies,and promoting precision diagnosis and treatment systems based on gender differences,and to form a three-dimensional diagnosis and treatment and research system that covers biomarkers,social role assessment,and TCM constitution identification,in order to provide a new theoretical framework and a practical pathway for the precise medical treatment of depression.

Depression is a highly heterogeneous psychiatric disorder with complex pathogenesis influenced by the interplay of biological,psychological,and social-environmental factors.Based on the 2021 edition of the Chinese Guidelines for the Prevention and Treatment of Depressive Disorders,which explicitly identify gender as a significant risk factor for depression onset,this paper systematically reviews the gender-differentiated pathogenesis and therapeutic advances in depression from both traditional Chinese medicine(TCM)and Western medical perspectives.In Western medicine,a large number of studies have demonstrated the sex-specific mechanism of estrogen/testosterone fluctuations and monoamine transmitter system regulation.While in TCM,although the constitution theory proposes that there are significant gender differences in congenital constitution and that qi depression and qi deficiency are associated with susceptibility to depression,current evidence primarily relies on cross-sectional surveys and lacks validation through high-quality RCTs.Compared with Western medicine,the direct research on gender-differentiated antidepressant effects in TCM remains relatively underdeveloped.In future study,it may be possible to deepen and improve the research on anti-depression in TCM from the biological markers of particular constitutions in the gender dimension.This paper advocates establishing a bio-psycho-social integrated intervention model,advancing mechanistic exploration through prospective cohort studies and multi-omics technologies,and promoting precision diagnosis and treatment systems based on gender differences,and to form a three-dimensional diagnosis and treatment and research system that covers biomarkers,social role assessment,and TCM constitution identification,in order to provide a new theoretical framework and a practical pathway for the precise medical treatment of depression.

Objective:This study aimed to explore the utility of transcutaneous electrical acupoint stimulation (TEAS) combined with skin sympathetic response (SSR) in assessing the effectiveness of perigastric autonomic nerve preservation during radical gastrectomy.Methods:A retrospective cohort analysis was conducted involving 221 patients who underwent laparoscopic radical gastrectomy at the Department of Gastric Surgery, Taizhou People's Hospital, affiliated with Nanjing Medical University, between June 2022 and September 2024. The cohort comprised 109 patients who underwent laparoscopic radical total gastrectomy without autonomic nerve preservation (total gastrectomy without nerve preservation group). Additionally, 112 patients underwent laparoscopic radical distal gastrectomy, including 34 patients who received autonomic nerve preservation (nerve preservation group) and 78 patients who did not (without nerve preservation group). TEAS was administered at the Zusanli and Tianshu acupoints one day before and one day after surgery, during which SSR latency and voltage amplitudes in the upper and lower extremities were recorded and compared across groups. Differences in SSR latency and voltage amplitude between the nerve preservation and non-nerve preservation groups of the distal gastrectomy cohort were also analyzed. Further, TEAS was applied at the same acupoints for 15 minutes on the 1st, 2nd, and 3rd postoperative days, and changes in intestinal sounds and intestinal functional recovery time were monitored. Surgical parameters, including operative duration, intraoperative blood loss, and harvested lymph node, were documented. Postoperative inflammatory indicators, including interleukin-6 (IL-6), C-reactive protein (CRP), procalcitonin (PCT), and the incidence of anastomotic leakage, were evaluated. At three months postoperatively, gastroscopy was performed to assess residual gastric food and bile reflux. Additionally, the prognostic nutritional index (PNI) was evaluated across all patient groups.Results:Following total gastrectomy, TEAS of Zusanli combined with arms' SSR revealed a latency of (23 59.71±410.55) ms and a voltage amplitude of (0.43±1.67) mV; for the legs, latency was (2 596.88±369.01) ms and voltage amplitude was (0.25±0.08) mV. TEAS of Tianshu combined with arms' SSR demonstrated a latency of (2 746.47±224.37) ms and a voltage amplitude of (0.31±0.14) mV; for the legs, latency was (2 891.90±193.61) ms and voltage amplitude was (0.19±0.72) mV. Postoperative latency was significantly prolonged, and voltage amplitude was markedly reduced (all P < 0.01). In the distal gastrectomy with nerve preservation group, TEAS of Zusanli combined with arms' SSR showed a latency of (1 668.04±261.91) ms and a voltage amplitude of (0.78±0.26) mV; for the legs, latency was (1 568.86±220.09) ms and voltage amplitude was (0.61±0.24) mV. TEAS of Tianshu combined with arms' SSR demonstrated a latency of (1 519.36±206.99) ms and a voltage amplitude of (0.66±0.34) mV; for the legs, latency was (2 004.80±508.53) ms and voltage amplitude was (0.55±0.28) mV. In the distal gastrectomy without nerve preservation group, TEAS of Zusanli combined with arms' SSR revealed a latency of (2 385.95±710.27) ms and a voltage amplitude of (0.23±0.11) mV; for the legs, latency was (2 506.81±779.37) ms and voltage amplitude was (0.26±1.29) mV. TEAS of Tianshu combined with arms' SSR indicated a latency of (2 697.78±385.55) ms and a voltage amplitude of (0.21±0.14) mV; for the legs, latency was (2 949.14±506.61) ms and voltage amplitude was (0.17±0.11) mV. The group without nerve preservation exhibited significantly prolonged latencies and reduced voltage amplitudes (all P<0.01). No statistically significant differences were observed between the groups in operative time, intraoperative bleeding, the number of dissected lymph nodes, inflammatory indicators (IL-6, CRP, PCT) at 3 days postoperatively, or anastomotic leakage rates (all P>0.05). In the group without nerve preservation, bowel sounds on postoperative days 1, 2, and 3 were (0.36±0.58), (1.04±0.97), and (1.74±1.10) times/min, respectively, with bowel function recovery time of (62.24±9.91) hours. The PNI at 3 months postoperatively was (37.42±3.01). Incidences of food residue in the residual stomach and bile reflux were 21.79% (17/78) and 29.49% (23/78), respectively. In the group with nerve preservation, bowel sounds on postoperative days 1, 2, and 3 were (0.76±0.82), (2.03±1.34), and (3.71±1.27) times/min, respectively, with bowel function recovery time of (44.94±8.05) hours. The PNI at 3 months postoperatively was (41.34±3.40). Incidences of food residue and bile reflux were 5.88% (2/34) and 11.76% (4/34), respectively. Statistically significant differences were observed between the groups (all P < 0.05). Conclusion:TEAS of Zusanli and Tianshu combined with SSR provides an objective measure for assessing the preservation of perigastric autonomic nerves during radical gastrectomy.

Objective To construct an enhancer-based prognostic risk prediction model for non-small cell lung cancer (NSCLC) by integrating DNA methylome data and transcriptome data. Methods The weighted gene co-expression network analysis (WGCNA) was used to identify NSCLC related genes from the differentially methylated positions (DMPs) of enhancers. Based on the transcriptome data,the prognostic risk prediction model was constructed using LASSO-Cox regression algorithm. Results Through the analysis on DNA methylome data of NSCLC,19784 DMPs were obtained and their distribution patterns were characterized,including 6089 DMPs of enhancers. WGCNA analysis screened 79 highly correlated DMPs of enhancer with NSCLC from the 6089 DMPs. After analyzing the target genes of 79 DMPs with LASSO-Cox regression based on the transcriptome data,10 genes were used to construct a prognostic risk prediction model. The prognostic risk prediction model was evaluated by calculating the areas under the curve (AUC) of 3-,5-,and 10-year time-dependent receiver operating characteristic (ROC) curves in training set and validation set;and the results showed that the 3-,5-,and 10-year AUC in training set and validation set were all higher than 0.7. Finally,a nomogram was constructed to predict the 3-,5-,and 10-year survival probabilities of NSCLC. Conclusion This study provides new insights into the role of enhancers in NSCLC and has the potential to improve the prognosis by guiding personalized treatment decisions.

Objective:To investigate the glymphatic system dysfunction and white matter microstructural damage in type 2 diabetic mellitus patients with diabetic peripheral neuropathy (DPN), and to identify the early diagnostic imaging biomarkers.Methods:Thirty-one DPN patients and 31 type 2 diabetes mellitus (T2DM) patients who attended the First People's Hospital of Yancheng from March 2022 to October 2023 were included. In addition, 40 healthy controls (HC) were recruited. All subjects underwent 3.0T MRI scan with diffusion tensor imaging and 3D-T1WI sequences, and the diffusion tensor imaging analysis along the perivascular space(DTI-ALPS) index, perivascular space volume fraction in white matter(PVSVF-WM) and peak width of skeletonized mean diffusivity (PSMD) were calculated. SPSS 26.0 software was used to perform one-way ANOVA, t-tests, and Chi-square tests to compare clinical data and imaging indicators among the three groups. Partial correlation analysis was used to explore the relationships between DTI-ALPS index, PVSVF-WM, PSMD and clinical indicators in DPN patients. Finally, receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic value of DTI-ALPS index, PVSVF-WM, and PSMD for DPN. Results:The DPN group(1.46±0.19)had considerably lower DTI-ALPS index than the T2DM group (1.59±0.14) and HC group (1.60±0.17) (both P<0.05, Bonferroni correction). The DPN group (1.44±0.11) had significantly higher PVSVF-WM than both the T2DM group (1.35±0.14) and HC group (1.26±0.13) (both P<0.05, Bonferroni correction). The DPN group (1.84±0.31) and the T2DM group (1.83±0.25) had higher PSMD than HC group (1.60±0.24) (both P<0.05, Bonferroni correction), but the difference between the DPN group and the T2DM group was not statistically significant ( P>0.05). The DTI-ALPS index in the DPN group were negatively correlated with PSMD ( r=-0.379, P=0.035). The DTI-ALPS index was negatively correlated with the Toronto clinical scoring system (TCSS) score ( r=-0.456, P=0.01), while PSMD was positively correlated with TCSS scores ( r=0.686, P<0.001) in DPN group. The ROC curves showed that the area under the curve (AUC) was 0.777 ( P<0.001) for the combined diagnosis of DPN with the DTI-ALPS index, PVSVF-WM and PSMD. Conclusion:DPN patients exhibit glymphatic system dysfunction and white matter microstructural damage. The DTI-ALPS index and PSMD can serve as objective markers for assessing DPN severity. The combination of glymphatic system function indicators and white matter microstructural damage markers has moderate diagnostic value for peripheral neuropathy in T2DM patients.

Objective To explore the biological mechanisms of isorhamnetin(ISO)inhibition of breast cancer(BC)progression and effects on paclitaxel sensitivity by in vivo and in vitro experiments.Methods The effects of ISO on MDA-MB-231 cell viability,migration,invasion and apoptosis were explored by CCK-8,scratch,Transwell invasion and apoptosis assays.ISO biological functions were analyzed and core target genes were identified by genome-wide microarrays,functional enrichment and protein-protein interactions(PPI).CYP1B1 expression characterization and prognosis in BC were assessed by quantitative Real-time polymerase chain reaction(qRT-PCR),Western blotting(WB),and Kaplan-Meier plotter database.The effects of CYP1B1 overexpression on MDA-MB-231 cell viability,migration,invasion and apoptosis were explored by CCK-8,scratch,Transwell invasion and apoptosis assays.The effects of ISO and CYP1B1 on BC tumor growth were analyzed by establishing a subcutaneous graft tumor animal model and verified by histological analysis with immunohistochemistry(IHC)and hematoxylin and eosin(HE)staining.The effects of ISO and CYP1B1 on NF-κB signaling were analyzed by qRT-PCR and WB.The effect of ISO combined with paclitaxel on BC progression was analyzed by in vitro and in vivo experiments.Results The results of CCK-8 assay showed that ISO inhibited the viability of MDA-MB-231 cells with an IC50 value of 11.93 μmol/L;the scratch,Transwell invasion and apoptosis assays confirmed that ISO inhibited the migration and invasion of MDA-MB-231 cells and promoted apoptosis(P＜0.05).Volcano plot showed a total of 80 differentially expressed genes(DEGs),of which ISO promoted the expression of 27 genes and inhibited the expression of 53 genes.Gene set enrichment analyses showed that DEGs were mainly enriched in the signaling of organic hydroxyl compound metabolic process,inflammatory response,sterol metabolic process,and nuclear factor-κB(NF-κB).qRT-PCR,WB,and Kaplan-Meier plotter results showed that CYP1B1 mRNA and protein expression was increased in BC and mediated worse prognosis(P＜0.05).CCK-8,scratch,Transwell invasion and apoptosis assays showed that CYP1B1 overexpression enhanced MDA-MB-231 cell viability,migration and invasion,and inhibited apoptosis,which was reversed by the addition of ISO(P＜0.05).The results of in vivo experiments showed that ISO downregulated CYP1B1 expression and attenuated NF-κB signaling(P＜0.05).The results of in vitro and in vivo experiments showed that ISO combined with paclitaxel significantly inhibited BC cell viability and tumor growth(P＜0.05).Conclusion ISO inhibits BC malignant biological behavior by modulating the CYP1B1/NF-κB signaling axis,and ISO enhances paclitaxel sensitivity.