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.

Objective To evaluate the clinical value of optic nerve sheath diameter(ONSD)measured on thin-slice CT scan in the diagnosis and prognostic assessment of cerebral venous sinus thrombosis(CVST).Methods The clinical data of patients with CVST,who were admitted to the First Affiliated Hospital of Nanjing Medical University of China to receive treatment from January 1,2016 to December 31,2022,were retrospectively analyzed.The difference in ONSD was compared between CVST patients and normal population,the postoperative changes in ONSD was analyzed.Results A total of 49 patients with CVST(CVST group)and 49 normal persons having no brain disorders(control group)were enrolled in this study.In CVST group,the preoperative ONSD was(5.33±0.50)mm,which was significantly higher than(4.40±0.40)mm in control group(P＜0.001),the postoperative ONSD remarkably decreased to(4.98±0.59)mm(P＜0.01).The difference value between postoperative ONSD and preoperative ONSD in the patients receiving pure anticoagulation treatment was not statistically significant different from that in the patients receiving endovascular treatment[(-0.43±0.22)mm vs.(-0.40±0.42)mm,P=0.84].The preoperative ONSD in the patients having intracranial hemorrhage and in the patients having no intracranial hemorrhage was(5.26±0.51)mm and(5.41±0.49)mm respectively(P=0.31),and the difference value between postoperative ONSD and preoperative ONSD was(-0.39±0.40)mm and(-0.45±0.25)mm respectively(P=0.66).At the three-month follow-up visit,the difference in ONSD between the patients having a good prognosis(mRS score being 0-2 points)and the patients having a poor prognosis was not statistically significant(P＞0.05).Conclusion ONSD that is measured on plain head CT scan can be used as a response indicator of elevated intracranial pressure in CVST patients,which can be used to monitor the changes in intracranial pressure before and after treatment,but its value in assessing the curative efficacy of different therapeutic methods needs to be further explored.

Objective:To compare the clinical efficacies of endovascular treatments in patients with acute basilar artery occlusion (ABAO) caused by large-artery atherosclerosis (LAA) and cardioembolism (CE).Methods:From March 2018 to February 2021, 104 patients with ABAO accepted endovascular treatments in Department of Neurology and Department of Interventional Radiology, Xuyi County People's Hospital of Huaian City were enrolled; these patients were classified into either a LAA group or a CE group according to Trial of ORG 10172 in Acute Stroke Treatment classification (TOAST). The differences in general data, procedure information, and clinical efficacies were compared between the 2 groups. Univariate and multivariate Logistic regression analyses were used to identify the influencing factors for poor prognosis.Results:In these 104 patients, 51 patients (49.0%) were into the LAA group and 53 patients (51.0%) into the CE group. Ninety-six patients (92.3%) acquired successful revascularization, and 35 patients (33.7%) had good prognosis (modified Rankin scale scores of 0-2) 90 d after surgery. LAA group had significantly lower percentage of patients with atrial fibrillation, significantly lower baseline National Institutes of Health Stroke Scale scores, statistically higher percentages of patients with lower and middle basilar artery occlusion and patients accepted rescued stenting, and statistically longer procedure time ( P<0.05). There were no significant differences between the two groups in terms of successful recanalization percentage, symptomatic intracranial hemorrhage incidence, and prognosis 90 d after surgery ( P>0.05). Age ( OR=0.935, 95%CI: 0.891-0.981, P=0.006) and semiquantitative scores of basilar artery based on computed tomography angiography ( OR=1.520, 95%CI: 1.180-1.959, P=0.001) were independent influencing factors for poor prognosis. TOAST etiology (LAA/CE) was not an independent influencing factors for poor prognosis ( OR=1.175, 95%CI: 0.461-2.933, P=0.736). Conclusion:There are differences in risk factors, vascular occlusion sites, endovascular treatment, and procedure time between patients with ABAO caused by LAA and CE; however, no obvious difference in clinical outcomes is noted, and there was no obvious correlation between stroke etiology and prognoses.