Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Attempts have been made to modulate motor sequence learning (MSL) through repetitive transcranial magnetic stimulation, targeting different sites within the sensorimotor network. However, the target with the optimum modulatory effect on neural plasticity associated with MSL remains unclarified. This study was therefore designed to compare the role of the left primary motor cortex and the left supplementary motor area proper (SMAp) in modulating MSL across different complexity levels and for both hands, as well as the associated neuroplasticity by applying intermittent theta burst stimulation together with the electroencephalogram and concurrent transcranial magnetic stimulation. Our data demonstrated the role of SMAp stimulation in modulating neural communication to support MSL, which is achieved by facilitating regional activation and orchestrating neural coupling across distributed brain regions, particularly in interhemispheric connections. These findings may have important clinical implications, particularly for motor rehabilitation in populations such as post-stroke patients.
Humans ; Transcranial Magnetic Stimulation ; Motor Cortex/physiology* ; Male ; Electroencephalography ; Neuronal Plasticity/physiology* ; Female ; Adult ; Evoked Potentials, Motor/physiology* ; Young Adult ; Learning/physiology*

OBJECTIVE: To explore whether hydrocortisone can improve the prognosis of patients with severe community-acquired pneumonia (sCAP) by Meta-analysis. METHODS: Randomized controlled trial (RCT) on hydrocortisone in the treatment of sCAP were extracted from the database including PubMed, Cochrane library, Web of Science, and Embase, and the search time was up to April 29, 2023. The patients in the standard treatment group received standard treatment such as antibiotics and supportive care, while those in the hydrocortisone group received hydrocortisone treatment on the basis of standard treatment. Meta-analysis was used to compare the mortality, duration of mechanical ventilation, mechanical ventilation rate and incidence of adverse reactions (hyperglycemia, gastrointestinal bleeding, secondary infection) between the two groups. The risk of literature bias was assessed. The studies that might have publication bias were corrected by the subtraction and complementation method. At the same time, trial sequential analysis (TSA) was conducted. RESULTS: A total of 5 RCTs involving 1 031 patients were finally enrolled, including 494 patients in the standard treatment group and 537 patients in the hydrocortisone group. Among the 5 studies, the research site of 2 studies was in the mixed ward. Considering the inclusion characteristics of the study population, there was doubt whether its research object was sCAP patients, which might have a certain impact on the results and introduce potential bias. Meta-analysis showed that the mortality in the hydrocortisone group was significantly lower than that in the standard treatment group [6.0% vs. 14.0%; odds ratio (OR) = 0.38, 95% confidence interval (95%CI) was 0.25-0.59, P < 0.01; I² = 9%]. The studies that were asymmetric were corrected by the reduction and supplementation method. Even after filling the missing studies, hydrocortisone could still reduce the death risk of the patient (OR = 0.49, 95%CI was 0.32-0.73, P < 0.01; I² = 31%). TSA showed that the average mortality of the standard treatment group was about 14.0%, and that of the hydrocortisone group was about 6.0%, with a relative risk reduction (RRR) = 57%. The calculated sample size was 699 cases, and the actual sample size was 1 031 cases. The actual sample size exceeded the required sample size, and the Z-curve crossed the O'Brien-Fleming boundary and the curve corresponding to P = 0.05, it meant that hydrocortisone could effectively reduce the mortality of sCAP. Compared with the standard treatment group, no statistical difference in the duration of mechanical ventilation was found in the hydrocortisone group [mean difference (MD) = -3.26, 95%CI was -6.72-0.21, P = 0.07; I² = 0%], but the 8-day mechanical ventilation rate was significantly lowered (19.5% vs. 55.4%; OR = 0.24, 95%CI was 0.12-0.45, P < 0.01; I² = 0%), and also no significantly difference was found in the incidence of hyperglycemia (54.3% vs. 44.6%, OR = 1.26, 95%CI was 0.56-2.84, P = 0.58; I² = 61%), gastrointestinal bleeding (2.5% vs. 3.6%; OR = 0.70, 95%CI was 0.34-1.46, P = 0.34; I² = 0%) and secondary infection (9.2% vs. 11.5%; OR = 0.46, 95%CI was 0.06-3.35, P = 0.45; I² = 53%). CONCLUSION Hydrocortisone can reduce the mortality rate of sCAP patients, decrease their need for mechanical ventilation, and does not increase the risk of hyperglycemia, gastrointestinal bleeding, or secondary infections.
Humans ; Hydrocortisone/therapeutic use* ; Community-Acquired Infections/drug therapy* ; Pneumonia/drug therapy* ; Randomized Controlled Trials as Topic ; Respiration, Artificial ; Community-Acquired Pneumonia

Objective To explore the necessity of placing an inferior vena cava filter(IVCF)during interventional therapy for acute lower extremity deep venous thrombosis(DVT)complicated with severe May-Thurner syndrome(MTS).Methods Patients with acute left lower extremity DVT complicated with severe MTS were retrospectively selected and divided into observation group(n=36)and control group(n=36)according to whether IVCF was implanted or not.Pulmonary embolism(PE)was evaluated using compu-ted tomography pulmonary angiography(CTPA).The improvement of the affected limb signs and the occurrence of PE symptoms during treatment were observed.The presence of trapped thrombus was checked during filter removal.The PE incidence,hospitaliza-tion costs,operation time,and hospital stay were compared between the two groups.Results Both groups had a higher thrombus clearance rate after interventional surgery,and the proportion of new small branch PE was lower without significant differences between the two groups(8.3%vs 5.6%,P=1.000).The signs of the affected limbs improved significantly,and no PE-related symptoms occurred during treatment.No obvious trapped thrombus was found when the filter was removed in the control group.Compared with the control group,the observation group had significantly reduced hospitalization costs and operation time(P<0.05).Conclusion For patients with acute lower extremity DVT complicated with severe MTS,omitting IVCF placement during interventional surgery does not increase the risk of PE and can reduce operation time and hospitalization costs.

Objective To evaluate the safety and efficacy of profunda femoral vein thrombosis clearance in endovascular treatment of acute lower extremity deep venous thrombosis (DVT). Methods From January 2022 to September 2023, clinical data of acute lower extremity DVT patients who underwent percutaneous mechanical thrombectomy (PMT) for profunda femoral vein thrombosis were retrospectively analyzed. The 12-month primary patency rate of iliofemoral vein and incidence of post-thrombotic syndrome(PTS) were analyzed. Results Twenty-two patients were included in the study, and all patients underwent PMT for profunda femoral vein thrombosis. Five patients were treated through the contralateral common femoral vein via crossover approach, and 17 patients were treated through the contralateral common femoral vein combined with the ipsilateral deep vein approach. The 12-month primary patency rate of iliofemoral vein was 90.9% (20/22), and the incidence of PTS was 9.1% (2/22). Conclusions For patients with acute lower extremity DVT undergoing endovascular treatment, PMT for profunda femoral vein thrombosis is safe and effective, achieving good primary patency of iliofemoral vein and low incidence of PTS.

Objective To explore the correlation between the pulmonary artery diameter(PAD),PAD/aortic diameter(AOD),right ventricular diameter(RVD),RVD/left ventricular diameter(LVD)measured on pulmonary artery CT angiography(CTPA)cross-sectional images and the degree of embolism,cardiac biomarkers in patients with medium-to-high risk acute pulmonary embolism(APE).Methods The clinical data of 53 patients with medium-to-high risk APE,who received interventional treatment at the Putian Municipal First Hospital of China From January 2021 to December 2023,were retrospectively analyzed.The PAD,PAD/AOD,RVD,and RVD/LVD were measured on CTPA cross-sectional images.The correlations of the above indexes with CT embolism index(CTEI),N terminal pro B type natriuretic peptide(NT-proBNP),and cardiac troponin Ⅰ(cTnⅠ)were analyzed.Results A weak-moderate positive correlation existed between PAD,RVD,RVD/LVD and CTEI(r=0.506,r=0.310,r=0.452 respectively,P＜0.001,P=0.024,P=0.001 respectively),while no correlation existed between PAD/AOD and CTEI(r=0.247,P=0.075).Compared with the NT-proBNP negative group,in the NT-proBNP positive group the values of PAD,PAD/AOD and RVD/LVD were higher(all P＜0.05),and there was no statistically significant difference in RVD value between the two groups(P＞0.05).A weak-moderate positive correlation existed between NT-proBNP and PAD,PAD/AOD,RVD,RVD/LVD(r=0.454,r=0.326,r=0.302,r=0.405 respectively,P=0.001,P=0.017,P=0.028,P=0.003 respectively).There were no statistically significant differences in PAD,PAD/AOD,RVD and RVD/LVD values between the cTnⅠ negative group and the cTnI positive group(all P＞0.05).No correlation existed between cTnⅠ and PAD,PAD/AOD,RVD,RVD/LVD(r=0.188,r=0.042,r=-0.021,r=0.139 respectively,and P=0.195,P=0.772,P=0.884,P=0.342 respectively).Conclusion CTPA cross-sectional quantitative indicators are helpful in evaluating the embolism degree of APE and right heart function,but it cannot be used to assess myocardial injury.

Objective:To compare the clinical characteristics of severe Mycoplasma pneumoniae pneumonia（SMPP）with bronchiolitis and consolidation to raise awareness.Methods:Retrospective analysis was conducted on children hospitalized at the first affiliated hospital of Xiamen University diagnosed with（SMPP）from February 2023 to January 2024.The children were divided into bronchiolitis group and large consolidation group based on their high-resolution CT imaging findings.Data on basic information，clinical features，auxiliary examination results，and bronchoscopy findings were analyzed.Results:This study included 415 pediatric patients，including 203 with bronchiolitis and 212 with large consolidation.The proportion of males，atopy rate，and first-degree relative atopy rate in the bronchiolitis group were higher，and the age of the bronchiolitis group was younger（ P<0.05）.The fever peak，incidence of fever，and low breath sound in the bronchiolitis group were lower，and the incidence of hypoxemia，wheezing，shortness of breath，inspiratory tri-concave signs，moist rales were higher than those in the consolidation group（ P<0.05）.The white blood cell counts，platelet counts，and lactate dehydrogenase were higher and the percentage of neutrophils，C-reactive protein，ferritin，D-dimer，and fibrinogen degradation products were lower in the bronchiolitis group than those in the consolidation group（ P<0.05）.The rate of 2 or more bronchoscopy procedures，and the proportion of longitudinal plica，mucus plug，and plastic in the consolidation group were higher than those in the bronchiolitis group（ P<0.05）.After three months of follow-up，there were 8 cases of bronchiolitis obliterans，including 7 cases in the bronchiolitis group and 1 case in the large consolidation group. Conclusion:If atopy，wheezing，and dyspnea are present in young children and preschool children with confirmed SMPP，they should be closely monitored for signs of bronchiolitis SMPP.Children with significant consolidation on imaging should have the possibility of various intrapulmonary and extrapulmonary problems taken into account.Appropriate treatment options should be implemented during the acute phase based on the imaging findings.

Objective To investigate the association between gout-related gene polymorphisms and clinical phenotypic heterogeneity among gout patients in the Foshan region,thereby providing a scientific basis for stratified clinical management.Methods A total of 125 gout patients diagnosed at the Foshan Hospital of Traditional Chinese Medicine between June 2022 and May 2025 were enrolled in this study.The collected data included demo-graphic characteristics,frequency of gout attacks,presence of tophi,levels of uric acid,creatinine,C-reactive protein(CRP),erythrocyte sedimentation rate(ESR),gout-related genes(ABCG2,SLC2A9,SLC22A12,MTHFR),and joint ultrasound findings.Group comparisons and rank correlation analyses were conducted to explore potential associations between gene polymorphisms and clinical heterogeneity.Results The male-to-female ratio was 11∶1;the mean age was(35.28±2.67)years;the mean disease duration was(6.03±0.68)years;and the mean frequency of acute attacks in the past 12 months was 4(2.0,7.25).Genotype distributions were as follows:ABCG2:wild-type(C/C),23.8%;heterozygous(C/A),53.2%;homozygous(A/A),23%.SLC2A9:wild-type(A/A),24.6%;heterozygous(A/G),50%;homozygous(G/G),25.4%.SLC22A12:wild-type(A/A),4.8%;heterozygous(A/C),31.7%;homozygous(C/C),63.5%.MTHFR:wild-type(C/C),68.3%;heterozygous(C/T),28.6%;homozygous(T/T),3.2%.Rank correlation analysis revealed that SLC2A9 polymorphisms were significantly correlated with tophi formation(ρ=0.193,P=0.031)and crystal deposition on ultrasound(ρ=0.202,P=0.025).SLC22A12 polymorphisms were associated with hypertension(ρ=0.269,P=0.003)and diabetes(ρ=0.200,P=0.026).MTHFR polymorphisms showed a correlation with diabetes(ρ=0.224,P=0.012).Conclusions Polymorphisms in SLC2A9,SLC22A12,and MTHFR are significantly linked to clinical phenotypic heterogeneity among gout patients.Genetic testing could facilitate the early identification of individuals at high risk for complications and support the development of stratified and individualized treatment approaches.

Objective To explore the necessity of placing an inferior vena cava filter(IVCF)during interventional therapy for acute lower extremity deep venous thrombosis(DVT)complicated with severe May-Thurner syndrome(MTS).Methods Patients with acute left lower extremity DVT complicated with severe MTS were retrospectively selected and divided into observation group(n=36)and control group(n=36)according to whether IVCF was implanted or not.Pulmonary embolism(PE)was evaluated using compu-ted tomography pulmonary angiography(CTPA).The improvement of the affected limb signs and the occurrence of PE symptoms during treatment were observed.The presence of trapped thrombus was checked during filter removal.The PE incidence,hospitaliza-tion costs,operation time,and hospital stay were compared between the two groups.Results Both groups had a higher thrombus clearance rate after interventional surgery,and the proportion of new small branch PE was lower without significant differences between the two groups(8.3%vs 5.6%,P=1.000).The signs of the affected limbs improved significantly,and no PE-related symptoms occurred during treatment.No obvious trapped thrombus was found when the filter was removed in the control group.Compared with the control group,the observation group had significantly reduced hospitalization costs and operation time(P<0.05).Conclusion For patients with acute lower extremity DVT complicated with severe MTS,omitting IVCF placement during interventional surgery does not increase the risk of PE and can reduce operation time and hospitalization costs.