Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

Objective:To compare the early effect of water sac blocking and Heartstring for proximal anastomosis of the calcific ascending aorta.Methods:The data of 400 consecutive patients undergoing elective off-pump coronary artery bypass grafting(OPCABG) in Beijing Anzhen Hospital from January 2022 to June 2022 were retrospectively analyzed. 46 patients with calcific ascending aorta including 40 males and 6 females, with the age ranged from 53 to 73 years and an average of(65.2±5.1) years, who were revealed by preoperative chest CT scan and intraoperative palpation. According to the method of proximal anastomosis, the patients were divided into 2 groups: water sac blocking group(n=19) and Heartstring group(n=27). The effect of preventing postoperative stroke was compared by counting the incidence of postoperative stroke. The efficacy of the 2 methods was compared by detecting the flow and pulsatility fraction of the saphenous vein trunk during surgery, observing the dynamic changes of the electrocardiogram and cTnI level within 48h after the surgery, and reviewing the coronary CTA 3 months after discharge.Results:There was no perioperative death, and all the patients were discharged 4-13 days postoperatively. No adverse events such as stroke and malignant ventricular arrhythmia occurred during perioperative period. 1 patient in each group developed low cardiac output syndrome postoperatively, and both improved after IABP placement. 1 patient in Heartstring group developed acute inferior myocardial infarction, which was improved after IABP placement. Coronary CTA 3 months after operation showed that there was no proximal anastomotic stenosis in both groups.Conclusion:There is no significant difference between the 2 proximal anastomosis methods in preventing stroke after OPCABG in patients with ascending aortic calcification. Compared with Heartstring, water sac blocking does not increase the risk of proximal anastomotic stenosis. In addition, water sac blocking does not require expensive consumables, which is especially suitable for patients with limited funds and can be generalized.

Objective:To explore the clinical value of aspirin combined with atorvastatin in the prevention of new onset atrial fibrillation after off-pump coronary artery bypass grafting (OPCABG).Methods:208 patients with coronary artery bypass grafting in our hospital from June 2019 to June 2021 were selected as the research subjects and divided by a random number table method into groups. The control group (104 cases) was treated with aspirin before operation, and the observation group (104 cases) was treated with aspirin and atorvastatin before operation. ECG monitoring was carried out continuously for 7 days of patients in the two groups, and the occurrence and duration of AF were recorded. The clinical therapeutic efficacy, incidence and adverse reactions of AF, left atrial diameter and high-sensitivity C-reactive protein (hs-CRP) level were observed before and after treatment.Results:The incidence of AF in the observation group was significantly lower than that in the control group, the difference was statistically significant ( P<0.05). There was no statistical significant difference in the starting time of AF between the two groups after operation ( P>0.05). The duration of AF in the observation group was better than that in the control group, the difference was statistically significant ( P<0.05). Before treatment, there was no statistical significant difference in left atrial diameter and hs-CRP level between the two groups ( P>0.05). After treatment, the left atrial diameter in the observation group returned to that before treatment, and there was no statistical significant difference in the same group ( P>0.05). The left atrial diameter in the control group was higher than that before treatment, and there was statistical significant difference in the same group ( P<0.05). The level of hs-CRP was lower than that in the control group, the difference was statistically significant ( P<0.05). There were no adverse reactions in both groups. Conclusion:Aspirin combined with atorvastatin has a significant effect in preventing new onset AF after OPCABG. It can reduce the incidence of postoperative AF, shorten the duration of AF, effectively control the inner diameter of left atrium, reduce the degree of postoperative inflammatory reaction, and has no adverse effects. It is worthy of clinical application.

CRISPR-Associated Protein 9 ; Gene Editing ; CRISPR-Cas Systems/genetics*

Objective:To investigate the early effect of different antithrombotic therapy in patients with coronary endarterectomy(CE) combined with off-pump coronary artery bypass grafting(OPCABG).Methods:Between January and December 2021, 154 consecutive patients including 120 males and 34 females with the age ranged from 39 to 78 years and an average of(62.6±7.2) years who underwent CE+ OPCABG were evaluated retrospectively. According to the postoperative anticoagulant therapy, patients were divided into two groups: Aspirin+ low molecular weight heparin group(n=81, LMWH group) and Aspirin+ ticagrelor group(n=73, ticagrelor group). The data of both preoperative and postoperative hemoglobin level and blood transfusion after the surgery were collected. The dynamic changes of electrocardiogram and cTnI level were observed within 48 h after the surgery.Results:There was no perioperative death, and all the patients were discharged 5-13 days postoperatively. After the initiation of anticoagulant therapy, the lowest hemoglobin value in the LMWH group and ticagrelor group was(88.3±14.6)g/L vs.(89.5±11.6)g/L( P>0.05), blood transfusion was performed in 8 vs. 5 patients with hemoglobin below 70g/L( P>0.05), peak cTnI within 48 h of surgery was 850.55(410.63, 1 662.63)pg/ml vs. 1 184.60(667.50, 3 169.63)pg/ml( P<0.05), the number of patients with perioperative myocardial infraction within 48h after the surgery confirmed by electrocardiogram was 2(2.5%) vs.2(2.5%), P>0.05. Conclusion:There was no significant difference between the two anticoagulant treatments in preventing perioperative myocardial infarction after CE+ OPCABG surgery. LMWH did not increase the risk of postoperative bleeding compared with ticagrelor. In addition, aspirin+ LMWH reduced the levels of peak TnI within 48 h of surgery, which may be associated with better long-term postoperative outcomes, but further research is needed to confirm this.

Objective:To discuss the clinical efficacy of Xuesusheng granule for cancer related fatigue （CRF） deficiency of both Qi and blood in clinical practice， and to investigate its effect on immune function and quality of life. Method:According to random number table method， 118 patients were divided into observation group （59 cases） and control group （59 cases）. Patients in control group got Ejiao Huangqi oral liquid， 10-20 mL/time， 2 times/day. Patients in observation group got Xuesusheng granule， 10 g/time， 3 times/day. The treatment was continued for 8 weeks in both groups. Before and after treatment， scores of cancer fatigue scale （CFS）， functional assessment of cancer therapy （FACT） and Qi and blood deficiency syndrome were graded， and degree of fatigue was discussed with brief fatigue inventory scale-Chinese （BFI-C）. Levels of white blood cell count （WBC）， neutrophil count （NEU）， platelet count （PLT）， red blood cell count （RBC）， and hemoglobin （Hb） were compared before and after treatment.T lymphocyte subsets of （CD3⁺， CD4⁺， CD8⁺） levels， natural killer （NK） cells， interleukin-1（IL-1）， IL-6， IL-8 and tumor necrosis factor -α （TNF -α） were also detected， and the safety was evaluated. Result:After treatment the scores of each factor in CFS scale and the total score of CFS in the observation group were lower than those in the control group （P<0.01）， and the degree of fatigue was lower than that in control group （Z=2.101， P<0.05）. The total score of FACT and the scores of four dimensions of physiology， society/family， emotion and function in the observation group were lower than those in the control group （P<0.01）. Levels of WBC， NEU， RBC and Hb in the observation group were higher than those in the control group （P<0.01）. Scores of BFI-C， deficiency of Qi and blood were lower than those in control group （P<0.01）. Levels of NK， CD3⁺， CD4⁺ and CD4⁺/CD8⁺ in the observation group were all higher than those in the control group （P<0.01）， while the IL-1， CD8⁺， IL-6， IL-8 and TNF-α levels in observation group were lower than those in the control group （P<0.01）. Not observed， there was no adverse reaction related to Xususheng granule. Conclusion:Xuesusheng granule can improve the symptoms of fatigue， reduce the degree of fatigue， improve the quality of life， reduce the degree of bone marrow suppression， improve immune function， and regulate immune inflammatory factors with high clinical efficacy in the use for patients with CRF and deficiency of Qi and blood.

With the appearance of the disadvantages of traditional tumor treatment, immunotherapy has entered people′s horizons as modern emerging treatment strategies, among which plant polysaccharides have received much more attention due to their antitumor activity and significant immunomodulatory effects. Tumor-associated macrophages (TAMs), as a component of tumor microenvironment, are important factors affecting tumors, and the regulation of TAMs by plant polysaccharides is one of the effective immunotherapy to treat tumor. In this review, we mainly described the regulation of TAMs by plant polysaccharides and the underlying mechanisms, and then gave an outlook on the research interests and the development of plant polysaccharides as immune adjuvants, aiming to provide reference for the study of plant polysaccharides in the immunotherapy for tumors.

Objective:To describe a distal anastomosis support (DAS) technique, and retrospectively investigate the effect of DAS on the mid-term graft patency of patient with small posterior descending artery.Methods:Between January and December 2016, 100 patients with triple-vessel disease and small PDA who continuously underwent off-pump coronary artery bypass grafting (OPCABG) (OPCABG group, n=50) and OPCABG with DAS for anastomosis of PDA grafted by saphenous vein (SVG) (OPCABG+ DAS group, n=50) were evaluated retrospectively. The dynamic changes of electrocardiogram and TnI level were observed within 48h after the surgery. All patients came back to follow-up visit 6th, 12th, 24th and 36th postoperative month. The primary endpoint was the graft failure (FitzGibbon B or O) of SVG-PDA on the follow-up CTA.Results:There was no death during the operation. There was no acute inferior wall myocardial infarction confirmed by electrocardiogram. Peak TnI within 48h of surgery was 0.74(0.98)ng/ml vs. 0.92(1.29)ng/ml, P>0.05, and the number of patients with peak TnI≥70×ULN was 3(6%, 3/50) vs.5(10%, 5/50), P>0.05. There was no postoperative death, and all the patients were discharged 5-15 days postoperatively. We found significantly improved cumulative graft patency in OPCABG+ DAS group at 36 months after operation [85.7%(42/49) vs. 68.0%(34/50), P<0.05). In multivariate logistic regression analysis, PDA with atherosclerotic lesions ( OR=6.513, 95% CI: 1.279-33.180, P=0.024), and peak TnI≥70×ULN within 48 h of surgery ( OR=5.948, 95% CI: 1.128-31.368, P=0.036) were independent predictors of graft failure, whereas concomitant DAS ( OR=0.222, 95% CI: 0.069-0.713, P=0.011) was significant protective factor. Conclusion:Concomitant DAS conferred superior mid-term patency of SVG-PDA in patients with small PDA. Adding the DAS procedure to OPCABG may be a promising surgical option for small PDA with atherosclerotic lesions.

Objective:To explore the role of genetic testing of VKORC1 and CYP2C9 in determining the dosage of warfarin after aortic valve replacement.Methods:A total of 172 patients receiving warfarin after aortic valve replacement were divided into a control group(86 cases) and an experimental(86 cases) group based on acceptance of genetic testing. In the experimental group, three loci of VKORC1 and CYP2C9 were tested by polymerase chain reaction-restriction fragment length polymorphism technique, and the initial dose of warfarin was determined based on the genetic testing results and warfarin oral-dose table recommended by U. S. Food and Drug Administration(FDA). In the control group, warfarin(3 mg/d) was used as the initial dose. The international normalized ratio(INR) of each patient was continuously monitored after medication. The percentages of patients meeting the target INR in the two groups at specific time points and at 3-month follow-up after discharge from the hospital were monitored, and the incidence of various adverse events was compared between the groups.Results:Based on the results of genetic testing, 68 patients received 3 mg/d(79.1%), 10 patients received 1.5 mg/d(11.6%), and eight patients received 6 mg/d(9.3%) as the initial dosages of warfarin in the experimental group. The percentages of the patients meeting the target INR on the third and sixth day of postoperative medication were 45.3% and 73.3%, respectively, in the experimental group, and 29.8% and 58.3%, respectively, in the control group( P<0.05). The INR critical values during hospitalization occurred in 2.3% in the experimental group and in 7.1% in the control group, while the percentage of the patients meeting the target INR after 3 months was 86.1% in the experimental group and 83.1% in the control group. Conclusion:Genetic testing may guide the selection of the initial dose of warfarin after heart valve replacement to rapidly achieve a stable dose.

Objective:To explore the correlation between serum high mobility group protein B1 (HMGB1) and severity of coronary artery disease.Methods:From January 2018 to March 2019, 170 patients who underwent coronary angiography and were definitely diagnosed with coronary heart disease in Beijing Anzhen Hospital were divided into single-vessel lesion group(65 cases), double-vessel lesion group(55 cases) and three-vessel lesion group(50 cases) according to the results of coronary angiography.Sixty healthy persons in the same period were set as the control group.The serum levels of HMGB1, endothelin-1, C-reaction protein (CRP), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) were detected, and the severity of coronary artery disease was evaluated according to Gensini score standard.Results:The serum HMGB1 of patients with single vessel disease was (7.35±0.75) μg/L, that of double vessel disease group was (11.56±1.16) μg/L, that of three vessel disease group was (14.36±1.46) μg/L, and that of control group was (3.22±1.52) μg/L.The difference between the two groups was statistically significant ( F=14.235, P<0.001). The serum endothelin-1 in single vessel disease group was (198.56±19.86) ng/L, that in double vessel disease group was (226.54±22.64) ng / L, that in three vessel disease group was (435.65±43.95) ng/L, and that in control group was (120.47±13.27) ng/L.The difference between the two groups was statistically significant ( F=16.337, P<0.001). The serum CRP of patients with single vessel disease was (6.21±0.61) ng/L, that of double vessel disease group was (8.54±0.84) ng/L, that of three vessel disease group was (11.36±1.16) ng/L, and that of control group was (3.39±1.56) ng/L.The difference between the two groups was statistically significant ( F=15.206, P<0.001). Serum LDL-C was (3.23±0.33) mmol/L in single vessel disease group, 4.12±0.42 mmol/L in double vessel disease group, (6.23±0.63) mmol/L in three vessel disease group and (2.25±1.45) mmol/L in control group.The difference between the two groups was statistically significant ( F=22.017, P<0.001). Serum HDL-C was (4.02±0.42) mmol/L in single vessel disease group, (2.35±0.25) mmol/L in double vessel disease group, (1.79±0.29) mmol/L in three vessel disease group and (4.60±1.69) mmol/L in control group.The difference between the two groups was statistically significant ( F=18.564, P<0.001). The Gensini score of single vessel disease group was (10.36±2.26), that of double vessel disease group was (16.74±1.04) and that of three vessel disease group was (23.36±2.36). The difference between the two groups was statistically significant ( F=23.014, P<0.001). The levels of HMGB1, endothelin-1, CRP and LDL-C in patients with coronary heart disease were significantly higher than those in the control group, while the levels of HDL-C were significantly lower than those in the control group (all P<0.05). The higher the number of diseased vessels, the higher the levels of HMGB1, endothelin-1, CRP, LDL-C and Gensini score, the lower the level of HDL-C.Multiple linear regression analysis showed that HMGB1, endothelin-1, CRP and LDL-C were risk factors of Gensini score (standard coefficient was 0.480, 0.087, 0.173, 0.197, t=8.351, 9.047, 12.476, 11.692, all P<0.01); HDL-C level was a protective factor of Gensini score (standard coefficient -0.352, t value was 16.582, P<0.001). Pearson linear correlation analysis showed that serum HMGB1 level was positively correlated with endothelin-1, CRP and LDL-C ( r=0.536, 0.659, 0.724, all P<0.05), and negatively correlated with HDL-C ( r=-0.669, P<0.05). Conclusion:There are obvious inflammatory reaction and lipid metabolism disorder in patients with coronary heart disease.The level of HMGB1 in peripheral blood is closely related to the severity of coronary artery disease.