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.

Mechanical ventilation is commonly employed for respiratory support in patients with respiratory failure. Despite the optimization of ventilator parameters and treatment methods, mechanical ventilation can still lead to both acute and chronic lung injury in patients with acute respiratory distress syndrome (ARDS) as well as in those without ARDS, a phenomenon referred to as ventilator-induced lung injury (VILI). VILI can be categorized into four types: barotrauma, volumetric injury, atelectasis injury, and biotic injury. Among these, biotic injury, characterized by inflammation, plays a significant role in the pathogenesis of VILI. Numerous studies have investigated the inflammatory mechanisms underlying VILI; however, these mechanisms remain complex and not entirely understood. At present, clinical practice lacks specific prevention and treatment strategies for VILI, aside from the implementation of protective ventilation strategies. Long non-coding RNAs (lncRNA) are a category of non-coding RNA longer than 200 nucleotides. LncRNAs regulate physiological and pathological processes such as cell proliferation, apoptosis, inflammatory response, and immune regulation, this regulation occurs through mechanisms such as modulating gene activity, inhibiting specific states, assisting in transcription initiation, affecting pre-mRNA splicing modifications, influencing translation processes, and expressing biofunctional peptides. They play an important role in the course of multiple diseases. Studies have shown that compared with control animals and cell models, lncRNAs are differentially expressed in VILI animal models and cell stretch models. Experiments have verified that certain lncRNAs play a crucial role in the pathogenesis of VILI by regulating the expression of inflammatory factors, the transformation of macrophage types, neutrophil activation, and cell apoptosis. Given the adverse effects of VILI on mechanical ventilation in critically ill patients, the important role of lncRNAs in biological regulation, and the urgent need to explore more effective strategies for the prevention and treatment of VILI, this paper summarizes the mechanisms through which lncRNA contributes to the VILI process, and discusses its possibility as a diagnostic and therapeutic target of VILI, in order to provide a reference for the clinical treatment of VILI.
RNA, Long Noncoding ; Ventilator-Induced Lung Injury ; Humans ; Respiration, Artificial/adverse effects* ; Animals ; Respiratory Distress Syndrome ; Apoptosis

Objective:To analyze the effect and influencing factors of embolotherapy on headache in elderly patients with unruptured intracranial aneurysms.Methods:A retrospective analysis of clinical data of elderly patients(aged≥61 years)with unruptured intracranial aneurysms admitted to our hospital from January 2018 to December 2020 was performed.Headache assessment was performed by a quantitative 11-point headache scale in all patients preoperatively and at 6 months after endovascular treatment, and the difference between them was analyzed.Univariate analysis was applied to test the association between headache outcomes and clinical variables.Results:A total of 73 patients(mean age: 68.4 years old; age range: 61-86 years; 47 women)fulfilled the inclusion criteria.There were 53 patients(72.6%)who presented with preoperative headache(headache score≥1). Among them, 39 cases(73.6%)had an improvement in headache, 11(20.8%)remained unchanged, and 3(5.7%)aggravated, after endovascular treatment.The average preoperative headache score was 5(4, 6) vs.postoperative 3(1, 4), with statistical significance( Z=-5.036, P=0.000). Only the preoperative headache score was associated with outcomes of headache, and a higher headache score predicted a lack of headache relief( Z=-2.819, P=0.005). Conclusions:Embolotherapy of unruptured intracranial aneurysms can relieve headache in most elderly patients.Preoperative headache severity is correlated with postoperative headache outcomes.

Objective:To investigate the application value of electroencephalogram (EEG) combined with regional cerebral oxygen saturation (rSO 2) in monitoring cerebral perfusion during carotid endarterectomy (CEA). Methods:A retrospective analysis of clinical data of 42 patients with atherosclerotic carotid artery stenosis admitted to and accepted CEA in our hospital from January 2018 to December 2019 was performed. CEA was performed under EEG combined with rSO 2 monitoring. The efficacy and safety of EEG combined with rSO 2 in monitoring cerebral perfusion abnormalities during CEA were analyzed. Results:After carotid artery occlusion, 24 patients (57.1%) had normal EEG and rSO 2; 15 (35.7%) had abnormal changes of EEG, among whom 13 (31.0%) were accompanied by rSO 2 anomaly; 16 (38.1%) had abnormal rSO 2, among whom 13 (31.0%) were accompanied by EEG anomaly. Of these 18 patients with abnormal EEG and/or rSO 2 monitoring, 17 patients recovered after increasing their blood pressure and 1 patient recovered after diverter tube usage. Intraoperative EEG and rSO 2 monitoring results were consistent (Kappa=0.745, P=0.000). The positive rates of combined monitoring, EEG alone or rSO 2 alone were 42.9%, 35.7% and 38.1%, respectively. All patients were evaluated clinically and radiologically before discharge, and no new ischemic lesions or clinical symptoms were found. Conclusions:EEG and rSO 2 monitoring are well consistent in CEA; the combined monitoring can make up for the deficiency of single monitoring to increase surgical safety.

Objective:To explore the efficacy of remote programming after vagus nerve stimulation (VNS) in patients with refractory epilepsy.Methods:Thirty-four patients who received VNS in our hospital from October 2019 to October 2020 were chosen in our study. Among them, 19 patients accepted remote programming (remote programming group) and 15 patients regularly came to the outpatient clinic for regulation (outpatient regulation group). The seizure frequency, response rate (seizure frequency decreased by≥50%), McHugh grading, and incidence of postoperative complications between the 2 groups were compared 6 months after VNS.Results:The seizure frequency in the remote programming group and outpatient regulation group was 2 (0, 4) times/month and 4(1, 24) times/month, without significant difference ( Z=-1.602, P=0.105). The proportion of patients enjoying effective treatment in the two groups was 13/19 and 8/15, without significant difference ( P=0.781). Results of McHugh grading showed no significant difference between the two groups ( Z=-0.728, P=0.467). The proportion of patients with postoperative complications in the two groups was 3/19 and 2/15, without significant difference ( P=0.625). Conclusion:The remote programming after VNS is safe and effective, which can become an important complementary approach for outpatient regulation.

Objective:To explore the clinical efficacy of posterior short-segment internal fixation for the treatment of brucella spondylitis (BS).Methods:The medical records of 34 patients with BS admitted from January 2014 to June 2019 were retrospectively analyzed. There were 22 males and 12 females; the age was 52.3±10.6 years (range 35-72 years). On the basis of standardized use of antibacterial drugs, the lumbar spine posterior short-segment internal fixation was used. Twenty-nine cases underwent simple internal fixation, and posterolateral bone graft fusion, while 5 cases underwent primary debridement, autologous bone grafting and interbody fusion. Monitor erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and test tube agglutination test (SAT) were used to assess inflammation control. Imaging examinations of patients before operation, 1 month after operation, 3 months after operation, 6 months after operation, 1 year after operation to the last follow-up were analyzed to evaluate the condition of intervertebral fusion. The clinical efficacy evaluation was based on the pain visual analog scale (VAS), Japanese Orthopaedic Association (JOA) score, modified MacNab grading, and American Spinal Injury Association (ASIA) grading, as well as surgery-related complications.Results:The operation time of 34 patients was 104.64±16.72 min (range 65-145 min), the average hospital stay was 16.49±7.41 days (range 7-38 d), and the average postoperative follow-up time was 20.2 months (range 12-34 months). At the last follow-up, the ESR and CRP fell to the normal range, and the SAT was negative. At 3 months postoperatively, 11 cases (32.35%) reached Bridwell fusion criteria of grade II, 23 cases (67.65%) of grade III; 3 cases (8.82%) of grade I fusion at 6 months after surgery, 31 cases reached grade II fusion (91.18%); all reached grade I fusion at the last follow-up. After the operation, the symptoms of the waist or lower extremities were significantly relieved. The VAS score was 6.3±1.4 before the operation, 4.1±1.2 at 1 month after the operation, 2.7±1.4 at 3 months after the operation, 1.6±1.0 at 6 months after the operation, and 1.2±0.8 at the last follow-up. The JOA score before surgery was 13.8±2.4, 1 month after surgery 17.6±2.6, 3 months after surgery 21.7±3.1, 6 months after operation 4.9±2.7, and at the last follow-up 25.7±1.8. Compared with the preoperative time nodes of the above indicators, the differences were statistically significant. At the last follow-up, of the 12 patients (2 cases of grade C, 10 cases of grade D) with preoperative neurological dysfunction, 2 cases recovered from grade C to grade D, and 10 cases recovered from grade D to E; the excellent and good rate of modified MacNab grading reached 97.06% (33/34). No extradural hematoma, nerve damage, cerebrospinal fluid leakage and other surgical complications occurred. Only 1 case had wound infection complication, and the prognosis was good after active treatment. There were no recurrences during the follow-up period.Conclusion:On the basis of standardized antimicrobial treatment, posterior lumbar short-segment internal fixation is a safe and effective method for the treatment of BS, and good clinical effects can be obtained.

ObjectiveTo investigate the effect of kaempferol on the proliferation, migration, invasion, and apoptosis of human hepatoma Bel-7402 cells and related molecular mechanism. MethodsHepatoma Bel-7402 cells cultured in vitro were randomly divided into control group and low-, middle-, and high-concentration experimental groups. The experimental groups were treated with low-, middle-, and high-concentration kaempferol (25, 50, and 100 μmol/L), and the control group was treated with an equal volume of dimethyl sulfoxide. CCK-8 assay was used to observe the effect of kaempferol on the viability of Bel-7402 cells; plate colony formation assay was used to evaluate the effect of kaempferol on cell colony formation ability; wound healing assay and Transwell chamber were used to observe the effect of kaempferol on cell migration and invasion; Western blot was used to measure the expression of apoptosis- and cycle-related proteins. A one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between two groups. ResultsAfter 24 hours of treatment, the cell viability was 100.00%±2.72% in the control group and 75.70%±2.42%, 62.79%±2.45%, and 43.41%±2.11%, respectively, in the low-, middle-, and high-concentration experimental groups, and compared with the control group, the experimental groups had a significant reduction in cell viability (all P＜0.05). The number of cell colonies was 923.3±35.2 in the control group and 682.7±24.4, 464.0±22.0, and 327.3±14.0, respectively, in the low-, middle-, and high-concentration experimental groups, and compared with the control group, the experimental groups had a significant reduction in cell colony formation ability (all P＜0.05). After 24 hours of treatment, the relative migration rate was 100.00%±1.11% in the control group and 63.33%±1.16%, 51.72%±3.23%, and 37.18%±2.71%, respectively, in the low-, middle-, and high-concentration experimental groups, and the number of transmembrane cells was 212.0±3.0 in the control group and 134.0±2.0, 71.0±2.0, and 34.0±1.0, respectively, in the low-, middle-, and high-concentration experimental groups; compared with the control group, the experimental groups had significant reductions in relative migration rate and number of transmembrane cells (all P＜0.05). After 48 hours of treatment, compared with the control group, the low-, middle-, and high-concentration experimental groups had a significant reduction in the expression of the anti-apoptotic protein Bcl-2 (all P＜0.05), a significant increase in the expression of the pro-apoptotic protein Bax (all P＜0.05), and a significant reduction in the expression of C＜italic/＞yclinD1 (all P＜005). ConclusionKaempferol can inhibit the proliferation, migration, and invasion of human hepatoma Bel-7402 cells and promote the apoptosis of such cells, possibly by regulating the apoptosis proteins Bax and Bcl-2 and downregulating the expression of CyclinD1.

Objective To explore the efficacy of moderate dose bromocriptine by one-off oral administration in treatment of patients with non-acute prolactin (PRL) type pituitary adenoma.Methods Forty-three patients with definite diagnosis of non-acute prolactin type pituitary adenoma,admitted to our hospital from January 2016 to December 2017,were chosen in our study.All patients were administrated with 5 mg bromocriptine at 18 pm;the serum PRL levels were examined at 2,3 and 12 h after bromocriptine administration.The curative effects of these patients were judged by decline rate of PRL,and the curative effects of patients with different genders,different initial PRL levels and different ages were compared.Results In these 43 patients,bromocriptine showed excellent effect in 20 patients,obvious effect in 18 and invalid effect in 5.There were statistically significant differences in the efficacy of bromocriptine between different genders (P＜0.05).There were statistically significant differences in efficacy of patients with different genders after taking bromocriptine (P＜0.05).The female patients had obviously higher rate of obvious effect than the male patients.Patients with different initial PRL values had statistically significant differences in efficacy after taking bromocriptine (P＜0.05).Patients with PRL initial value of 40-200 ng/mL had significantly higher rate of obvious effect than patients with PRL initial value of ＞200 ng/mL.There was no significant difference in efficacy between patients ＜ 45 years old and patients＞45 years old (P＞0.05).Conclusion The treatment ofhyperprolactin caused by prolactin type pituitary adenoma with moderate dose bromocriptine by one-off oral administration is effective;female patients have obviously better effect than male patients;and for patients with initial prolactin＞200 ng/mL,the effect is better.

Objective To analyze the risk factors related to incidence of shunt dependent hydrocephalus in patients with intracranial aneurysmal subarachnoid hemorrhage so as to provide guidance for clinical diagnosis and treatment.Methods The clinical data were retrospectively analyzed of the 451 patients who had been treated in our hospital for ruptured intracranial aneurysmal subarachnoid hemorrhage from January 2013 to December 2016.Of them,67 were complicated with shunt dependent hydrocephalus and 384 were not.The 2 groups were compared in terms of related clinical variables.Multivariate Logistic regression was conducted to analyze risk factors associated with incidence of shunt dependent hydrocephalus.Results The proportions of patients ＞60 years old,intraventricular hemorrhage,posterior circulation aneurysm,acute hydrocephalus and central nervous system infection were significantly higher in the patients with complicated shunt dependent hydrocephalus than in those without (P＜0.05).There were significant differences between the 2 groups in Hunt-Hess grade and Fisher grade at admission (P＜0.05).Multivariate Logistic regression analysis revealed that posterior circulation aneurysm,acute hydrocephalus and central nervous system infection were independent risk factors for incidence of shunt dependent hydrocephalus in patients with intracranial aneurysmal subarachnoid hemorrhage.Conclusion If the patients with intracranial aneurysmal subarachnoid hemorrhage are complicated with posterior circulation aneurysm,acute hydrocephalus and central nervous system infection,they are more likely to develop shunt dependent hydrocephalus.