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:This meta-analysis was conducted to systematically evaluate the short-term efficacy and safety of indocyanine green fluorescence imaging guided laparoscopic liver tumor resection (FIGLTR).Methods:A systematic search was made for the literature on indocyanine green fluorescence image-guided laparoscopic hepatectomy in randomized, semi-randomized controlled trials and observational studies, and manually search published materials and conference papers in Chinese and English and trace references included in the literature. The retrieval period was up to September 2021. The quality of included studies was evaluated, then the meta-analysis was conducted using Review Manager 5.1 software.Results:Ten studies were included with 803 patients, including 341 in the FIGLTR group and 462 in the non-FIGLTR group. Meta results showed that: Compared to the traditional resection group, indocyanine green fluorescence imaging can significantly shorten the operative time ( MD=-22.61, 95% CI: -34.20--11.03, P<0.001), reduce intraoperative bleeding ( MD=-49.17, 95% CI: -84.99--13.36, P<0.01), shorter hospital stay ( MD=-0.89, 95% CI: -7.72--0.06, P<0.05), Improve the removal rate of R 0 edge ( OR=8.80, 95% CI: 1.96-39.44, P<0.05) and reduce the incidence of postoperative complications ( OR=0.55, 95% CI: 0.34-0.87, P<0.05) of laparoscopic liver tumor resection. There were no differences found in portal block time and transfusion rate. Conclusion:Indocyanine green fluorescence imaging technology provides a new way for safe and accurate laparoscopic resection of liver tumors.

Objective:To systematically evaluate the clinical effect of biliary stent combined with intra-biliary radiofrequency ablation and stent alone in the treatment of malignant obstructive jaundice.Methods:The PubMed, Cochrane library, Embase, HowNet, Wanfang, Weipu were systematically searched, the search time was up to February 2021. To collect and compare the clinical efficacy studies of combined intra-biliary radiofrequency ablation in the treatment of patients with malignant obstructive jaundice before biliary stent placement. After literature screening, data extraction and quality assessment conducted by two independent reviewers. Meta-analysis was performed with the patients' 1-year survival rate, 6-month patency rate after biliary stent operation, and comparative changes in postoperative complications as the main outcome indicators.Results:Finally, 9 studies were included, comprising 2 randomized controlled studies (RCT) and 7 retrospective studies, involving a total of 443 patients, with 211 cases in the biliary stent combined with intra-biliary radiofrequency ablation group and 232 cases in the stent alone group. The results of meta-analysis showed that in two joint groups compared with the stent alone group, in overall analysis, the rate of re-obstruction of the biliary tract decreased 6 months after stenting ( OR=0.24, 95% CI: 0.13-0.42) and 1-year survival rate increased ( OR=3.79, 95% CI: 2.08-6.90), the differences are statistically significant ( P<0.001), there was no statistical difference in the complications ( P=0.13). In ERCP group, the rate of re-obstruction of the biliary tract decreased 6 months after stenting ( OR=0.21, 95% CI: 0.08-0.55), and the 1-year survival rate significant increase ( OR=3.63, 95% CI: 1.76-7.48), the differences are statistically significant ( P<0.01). In PTCD group, the rate of re-obstruction of the biliary tract decreased 6 months after stenting ( OR=0.25, 95% CI: 0.12-0.51), and the 1-year survival rate significant increase ( OR=4.13, 95% CI: 1.42-12.03), the differences are statistically significant ( P<0.01). Conclusion:Compared with the stent-only group, the combined group is safe and effective in treating malignant obstructive jaundice.

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 targeting relationship between miR-377-5p and hypoxia inducible factor-1 (HIF-1α), and investigate the regulatory effect of miR-377-5p on proliferation, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells through vascular endothelial growth factor (VEGF) signaling pathway. Methods： ：The expression of miR-377-5p in 35 pairs of human HCC tissues and para-cancerous tissues was detected by qPCR. Then, HepG2 cells were divided into control group, mimic-NC group and miR-377-5pmimicgroup.qPCRwasusedto detect the transfection efficiency; the effects of miR-377-5p over-expression on proliferation and invasion of HepG2 cells were examined by EdU staining and Transwell assay, respectively; and the effect of miR-377-5p over-expression on the expressions of proliferation-related protein Ki-67, proliferating cell nuclear antigen (PCNA) and epithelial-mesenchymal transition (EMT) markers (E-cadherin and N-cadherin) were detected by Western blotting (WB); the effect of miR-377-5p over-expression on the expression of hypoxia inducible factor-1α (HIF-1α) in HepG2 cells was detected by qPCR and WB; and the targeting relationship between miR-377-5p and HIF-1α gene was determined by Luciferase reporter gene assay. Results: The expression of miR-377-5p in HCC tissues was significantly lower than that in para-cancerous tissues (P<0.01). Compared with the control group, the expression of miR-377-5p in HepG2 cells of miR-377-5p mimic group elevated significantly, and the proliferation, invasion and the expression of N-caderin proteins decreased,significantly (all P<0.01), while the expression of E-caderin increased significantly (P<0.01). At the same time, the mRNA and protein expressions of HIF-1α in miR-377-5p mimic group decreased significantly (P<0.01 or P<0.05). miR-377-5p targetedly inhibited the expression of HIF-1α gene and suppressed the activation of VEGF pathway (all P<0.05). Conclusion: miR-377-5p inhibits the proliferation, invasion and EMT of HepG2 cells via targetedly inhibiting HIF-1α expression and suppressing the activation of VEGF signaling pathway.

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.

ObjectiveTo investigate the clinical effect and safety of robot-assisted laparoscopic hepatectomy (RALH) versus open hepatectomy (OH) in the treatment of liver diseases. MethodsWeb of Science, PubMed, Cochrane Library, Embase, CNKI, CBM, VIP, and Wanfang Data were searched for Chinese and English articles on RALH versus OH in the treatment of liver diseases published up to February 2020. The quality of the articles included was assessed, and RevMan 5.1 was used to perform the meta-analysis. ResultsSeven studies were included, with a total of 754 patients (328 patients in the RALH group and 426 in the OH group). The meta-analysis showed that compared with the OH group, the RALH group had a significantly longer time of operation (mean difference ［MD］=59.41, 95% confidence interval ［CI］: 9.74-109.08, P=0.02), significantly higher blood transfusion rate (relative risk ［RR］=2.24, 95%CI: 1.04-4.82, P=0.04) and rate of hepatic portal occlusion (RR=2.27, 95%CI: 1.37-3.75, P=0.001), a significantly shorter length of hospital stay (MD=-3.87, 95%CI: -5.63 to -2.12,P＜0.001), and significantly lower overall incidence rate of postoperative complications (RR=0.58, 95%CI: 0.41-0.81, P=0.001) and incidence rates of major postoperative complications (RR=0.45, 95%CI: 0.22-0.91, P=0.03). There was no significant difference in intraoperative blood loss between the two groups (P＞0.05). ConclusionFor hepatectomy, RALF can shorten the length of hospital stay and reduce postoperative complications, creating conditions for minimally invasive hepatectomy and rapid recovery.

Objective: To investigate the clinical application of indocyanine green fluorescence imaging in open hepatectomy. Methods: A total of forty-five patients who underwent liver resection in Department of Hepatobiliary Surgery, Affiliated Hospital of Southwest Medical University from July 2017 to December 2018 were included in this prospective study. There were 26 males and 19 females, aged between 29 to 74 (51±10) years. Indocyanine green was injected intravenously 72~96 hours prior to surgery in all these patients. An intraoperative fluorescence imaging system was used to locate and remove the tumor, the liver parenchymal transection planes and surgical margins were detected by fluorescence again after tumor resection. The fluorescence profiles of the tumor specimens in relation to the tumor differentiation were analyzed. Results: Indocyanine green fluorescence imaging was performed in 45 patients. A total of 66 lesions were detected by preoperative CT (or MRI), abdominal ultrasound and intraoperative fluorescence imaging. After excision of the primary liver cancer, the surgical margins of the remnant liver stumps and fluorescence in the excised liver specimens were studied. Thirteen small lesions were found in 10 patients, most of which were located at the surgical margin, and the smallest tumors detected were less than 5 mm in diameter. Five venous cancer emboli were found in 5 patients, 3 of which were not detected by preoperative imaging examinations. The fluorescence profile images of the excised hepatocellular carcinoma specimens showed homogeneous fluorescence in most highly differentiated hepatocellular carcinoma, and partial fluorescence or ring fluorescence in moderately differentiated hepatocellular carcinoma. Conclusion Indocyanine green fluorescence imaging technology can identify liver surface lesions, as well as detect small residual lesions at the cutting edge and venous thrombus, which improves the efficiency of hepatocellular carcinoma resection.

Objective Transient brain function inhibition is a common symptom after mild brain injury,but some patients show persistent post-concussional syndrome (PCS).The aims of this study are to assess functional and causal connectivity of attention and default mode network using resting-state functional MR imaging (fMRI) to investigate the abnormal connectivity and its significance in PCS patients.Methods Resting-state fMRI data were collected from 23 PCS patients with attention disorders,admitted to our hospital from November 2015 to October 2016 and 21 age-,gender,and education-matched healthy controls recruited at the same period.The fMRI data were analyzed by group independent component analysis (ICA) toolbox to attention networks and default mode network (DMN).The components of the selected networks were compared in PCS and healthy controls to explore the changes of functional connectivity (FC).Granger causality analysis (GCA) was performed by taking the above significant brain areas as regions of interest (ROIs) to calculate bivariate coefficient of each pair of ROIs.Comparisons were performed to find the significant different causal connectivity of the two groups.Results In attention networks,the FC value of left frontal eye field (FEF),bilateral intraparietal sulcus (IPS),bilateral ventral prefrontal cortex (vPFC) and bilateral temporo-parietal junction (TPJ) was decreased.In DMN,the FC value of bilateral medial prefrontal cortex (mPFC) was reduced and bilateral precuneus (PCUN) was enhanced.Correlating GCA value,it was increased significantly from left FEF to left PCUN and IPS,while it was reduced from left PCUN and IPS to left FEF;and it was decreased from left IPS to left vPFC and increased from left TPJ to left PCUN.Conclusion The attention networks are restrained in resting state,which may influence the attention function in PCS patients;and the causal connection is altered in the above ROIs,and these changes may be related to inhibition of activation of default network to compensate for the loss of attention function by antagonistic effects in PCS patients.

ObjectiveTo explore the changes of degree attribute values and its significance of post-concussion syndrome (PCS) patients with tinnitus by the brain network research method based on graph theory.Methods34 PCS patients were chosen,including 17 PCS patients with bilateral tinnitus (PCS tinnitus group) and 17 PCS patients without tinnitus (PCS non-tinnitus group).Meanwhile,17 healthy individuals with the matched age,gender and educational background were recruited as the control.Degree attribute values of PCS patients with tinnitus were figured out with the brain network research method based on graph theory.Results(1)The degree attribute values of PCS patients without tinnitus at left orbital middle frontal gyrus (3.13±1.07),left thalamus (2.51±1.03),left superior temporal gyrus (3.67±1.31),right anterior cingulate cortex (3.13±1.25),right posterior cingulate cortex (2.13±1.08) and right supramarginal gyrus (4.46±1.35) were reduced compared with the control group (4.41±1.47,3.71±1.08,5.27±2.13,5.51±0.67,5.63±2.16 and 5.64±1.30) (P<0.05).The degree attribute values of PCS patients without tinnitus at left posterior cingulate cortex (5.87±1.06) and left gyrus lingualis (4.67±1.48) increased compared with the control group (4.41±1.46,3.21±1.27) (P<0.05).(2) The degree attribute values of PCS patients with tinnitus at left posterior cingulate cortex (3.37±1.54),left parahippocampal gyrus (3.41±1.62),left amygdala (2.25±1.43),left angular gyrus (4.17±1.02),left superior temporal gyrus (3.25±1.02),right thalamus (2.35±1.34),right Heschl gyri (3.97±1.62),right superior temporal gyrus (3.26±1.22),right cuneus (3.18±1.32) and right lingular lobe (3.26±1.42) were decreased,compared with the control group (4.41±1.46,5.27±2.13,3.71±1.08,5.63±2.61,5.64±1.30,3.43±1.33,5.63±2.16,5.13±1.64,5.51±0.67,4.24±0.63) (P<0.05).The degree attribute values of PCS patients with tinnitus at right posterior cingulate cortex (5.76±1.83),left MPFC (6.08±1.62) and right precuneus (6.08±1.06) were increased,compared with the control group (4.47±1.26,4.41±1.47,4.81±0.62) (P<0.05).(3)The degree attribute values of PCS patients with tinnitus at left MPFC,left amygdale,left parahippocampal gyrus,right Heschl gyri,right superior temporal gyrus,right cuneus and right lingular lobe were decreased,compared with PCS patients without tinnitus (P<0.05).The degree attribute values of PCS patients with tinnitus at right posterior cingulate cortex and left insular lobe increased,compared with PCS patients without tinnitus (P<0.05).ConclusionsPCS patients with tinnitus present the alteration of degree attribute in related brain network structure.The alteration in degree attribute of relevant brain zones in auditory system,limbic system and default network system may be important factors which result in tinnitus of PCS patients.