Objective To explore the molecular mechanism of Xiaojin Pills in the treatment of breast cancer using an integrated network pharmacology and experimental verification.Methods The chemical components and potential targets of Xiaojin Pills were obtained from TCMSP,TCM-ID,ETCM and SwissTargetPrediction databases.Breast cancer related targets were collected from GeneCards,OMIM and KEGG databases.The overlapped targets were imported into STRING database to analysis a protein-protein interaction(PPI).The key targets of PPI networks were screened based on node topology parameter values through Cytoscape 3.8.0.DAVID database was used to analyze the GO and KEGG pathway enrichment to build drug-chemical components-key targets-signaling pathway network.The breast cancer cell lines MDA-MB-231 and SK-BR-3 were used to study the effects of Xiaojin Pills extract on cell apoptosis,migration and invasion,and to verify the key pathway obtained by enrichment analysis.Results Totally 181 chemical components in Xiaojin Pills were obtained,including quercetin,myricetin,pinocembrin and β-sitosterol.615 potential targets were identified for the anti-breast cancer effects of Xiaojin Pills.After overlapping,170 key targets against breast cancer were identified based on the topological analysis,which included SRC,ERK1/2,AKT1,EGFR,etc.KEGG analysis enriched pathways including pathways in cancer,MAPK signaling pathway,endocrine resistance,PI3K-AKT signaling pathway,EGFR tyrosine kinase inhibitor resistance,apoptosis,and HIF-1 signaling pathway,which may play important roles in the therapeutic effects of Xiaojin Pills against breast cancer.GO enrichment was involved in protein phosphorylation,inflammatory response,negative regulation of apoptosis,and positive regulation of ERK1 and ERK2 cascades.Cell experiments showed that Xiaojin Pills further induced mitochondria-dependent apoptosis by inhibiting the activation of MAPK and PI3K-AKT pathways.At the same time,the expressions of ZO-1 and β-catenin increased,and the epithelial-mesenchymal transformation process was reversed to inhibit the metastasis of breast cancer cells.Conclusion The key targets and signaling pathways of Xiaojin Pills in the treatment of breast cancer are studied through network pharmacology combined with in vitro experiments,which provided a basis for further study of its pharmacodynamic material basis,mechanism of action and clinical application.

Background: Immunochemotherapy has demonstrated a promising efficacy for a variety of B-cell lymphoma but has limited efficacy for Epstein–Barr virus-positive (EBV +) diffuse large B-cell lymphoma (DLBCL) that is refractory or relapsed to conventional chemotherapy regimens. Considering higher programmed death-ligand 1 (PD-L1) expres‑ sion in the subset of patients with DLBCL with positive EBV, we speculated that PD-1 inhibitors plus chemotherapy may be an alternative regimen in patients with refractory/relapsed EBV + DLBCL. Methods: This retrospective study included six adult patients diagnosed with refractory EBV + DLBCL resistant to first-line immunochemotherapy regimens (R-CHOP). These patients received PD-1 inhibitors plus chemotherapy as second-line treatment. Results: The final analysis included six patients (four men and two women (median age, 50 years; range, 39–83 years)). Four patients were diagnosed with Epstein–Barr virus (EBV) + DLBCL, and two had DLBCL associated with chronic inflammation. Over a median follow-up of 20 months (range, 2–31 months), the objective response rate was 83% (5/6) and the complete remission rate was 67% (4/6). No severe immune-related adverse reactions occurred, and only a mild rash was reported, which did not necessitate the discontinuation of therapy. Conclusion The combination of PD-1 inhibitors and chemotherapy offers promising results as a second-line treat‑ ment for patients with refractory EBV + DLBCL that is resistant to first-line immunochemotherapy regimens. These preliminary findings warrant further investigation in larger clinical trials to validate the efficacy and safety of this therapeutic approach.

Background: Immunochemotherapy has demonstrated a promising efficacy for a variety of B-cell lymphoma but has limited efficacy for Epstein–Barr virus-positive (EBV +) diffuse large B-cell lymphoma (DLBCL) that is refractory or relapsed to conventional chemotherapy regimens. Considering higher programmed death-ligand 1 (PD-L1) expres‑ sion in the subset of patients with DLBCL with positive EBV, we speculated that PD-1 inhibitors plus chemotherapy may be an alternative regimen in patients with refractory/relapsed EBV + DLBCL. Methods: This retrospective study included six adult patients diagnosed with refractory EBV + DLBCL resistant to first-line immunochemotherapy regimens (R-CHOP). These patients received PD-1 inhibitors plus chemotherapy as second-line treatment. Results: The final analysis included six patients (four men and two women (median age, 50 years; range, 39–83 years)). Four patients were diagnosed with Epstein–Barr virus (EBV) + DLBCL, and two had DLBCL associated with chronic inflammation. Over a median follow-up of 20 months (range, 2–31 months), the objective response rate was 83% (5/6) and the complete remission rate was 67% (4/6). No severe immune-related adverse reactions occurred, and only a mild rash was reported, which did not necessitate the discontinuation of therapy. Conclusion The combination of PD-1 inhibitors and chemotherapy offers promising results as a second-line treat‑ ment for patients with refractory EBV + DLBCL that is resistant to first-line immunochemotherapy regimens. These preliminary findings warrant further investigation in larger clinical trials to validate the efficacy and safety of this therapeutic approach.

Background: Immunochemotherapy has demonstrated a promising efficacy for a variety of B-cell lymphoma but has limited efficacy for Epstein–Barr virus-positive (EBV +) diffuse large B-cell lymphoma (DLBCL) that is refractory or relapsed to conventional chemotherapy regimens. Considering higher programmed death-ligand 1 (PD-L1) expres‑ sion in the subset of patients with DLBCL with positive EBV, we speculated that PD-1 inhibitors plus chemotherapy may be an alternative regimen in patients with refractory/relapsed EBV + DLBCL. Methods: This retrospective study included six adult patients diagnosed with refractory EBV + DLBCL resistant to first-line immunochemotherapy regimens (R-CHOP). These patients received PD-1 inhibitors plus chemotherapy as second-line treatment. Results: The final analysis included six patients (four men and two women (median age, 50 years; range, 39–83 years)). Four patients were diagnosed with Epstein–Barr virus (EBV) + DLBCL, and two had DLBCL associated with chronic inflammation. Over a median follow-up of 20 months (range, 2–31 months), the objective response rate was 83% (5/6) and the complete remission rate was 67% (4/6). No severe immune-related adverse reactions occurred, and only a mild rash was reported, which did not necessitate the discontinuation of therapy. Conclusion The combination of PD-1 inhibitors and chemotherapy offers promising results as a second-line treat‑ ment for patients with refractory EBV + DLBCL that is resistant to first-line immunochemotherapy regimens. These preliminary findings warrant further investigation in larger clinical trials to validate the efficacy and safety of this therapeutic approach.

ObjectiveTo investigate the detoxification mechanism of Chebulae Fructus， Glycyrrhizae Radix et Rhizoma and Prepared Aconiti Kusnezoffii Radix Cocta， and their effective components ellagic acid， liquiritin and aconitine based on cardiac cytochrome P450 （CYP450） system. MethodIn in vivo experiments， rats were randomly divided into control group， prepared Aconiti Kusnezoffii Radix Cocta group （0.25 g·kg^-1）， Chebulae Fructus group （0.252 g·kg^-1）， Glycyrrhizae Radix et Rhizoma group （0.25 g·kg^-1） and combination group （0.25 g·kg^-1 Chebulae Fructus+0.25 g·kg^-1 Glycyrrhizae Radix et Rhizoma+0.25 g·kg^-1 prepared Aconiti Kusnezoffii Radix Cocta， with prepared Aconiti Kusnezoffii Radix Cocta as standard）. After 8 days of administration， creatine kinase （CK） and lactate dehydrogenase （LDH） in rats were detected to observe the pathological changes of heart tissue. Real-time PCR and Western blot were performed to detect the mRNA and protein expressions of CYP2J3， respectively. In in vitro experiments， control group， aconitine group， ellagic acid group， liquiritin group and combination group （aconitine+ellagic acid+liquiritin） were set， and their effects on cell number， DNA content， reactive oxygen species （ROS） and mitochondrial membrane potential （MMP） were detected by high content analysis. The changes in the mRNA and protein expressions of CYP2J3 were also observed. ResultIn vivo experiments， compared with the control group， the prepared Aconiti Kusnezoffii Radix Cocta group had increased CK and LDH in serum （P<0.05， P<0.01）， while the combination group had decreased activities of CK and LDH. Additionally， pathological staining results showed that Chebulae Fructus and Glycyrrhizae Radix et Rhizoma reduced the cardiac toxicity caused by prepared Aconiti Kusnezoffii Radix Cocta. Real-time PCR found that compared with the control group， prepared Aconiti Kusnezoffii Radix Cocta down-regulated the mRNA level of CYP2J3 （P<0.05）， while up-regulated that expression when used in combination with Chebulae Fructus and Glycyrrhizae Radix et Rhizoma （P<0.01）. The protein and mRNA translation levels were basically consistent. In vitro experiments， high content analysis revealed that there was a decrease in the cell number， DNA content and MMP fluorescence value of the aconitine group （P<0.01） and the combination group （P<0.05， P<0.01）， and the fluorescence value of the combination group was higher than that of the aconitine group. Moreover， aconitine down-regulated the mRNA level of CYP2J3 （P<0.05）， but the down-regulating ability of aconitine was reversed in the combination group （P<0.05）. ConclusionThe detoxification mechanism of combined Chebulae Fructus， Glycyrrhizae Radix et Rhizoma and prepared Aconiti Kusnezoffii Radix Cocta is mainly that the combination of ellagic acid， liquiritin and aconitine can up-regulate the expression of CYP2J3， and promote the metabolism of arachidonic acid （AA） to produce epoxyeicosatrienoic acids （EETs）， thus reducing the cardiac toxicity， and this effect may start from the transcriptional link.

Objective:To investigate the effects of Guiling Gao on body temperature, gastrointestinal motility, gastrointestinal hormones, Th1/Th2 cytokines and water metabolism in rats with damp-heat syndrome.Methods:Totally 60 SD rats were randomly divided into control group, model group, mosapride group, Guiling Gao low dose group (3.4 g/kg), medium dose group (6.8 g/kg) and high dose group (13.6 g/kg) according to random number table method, with 10 rats in each group. Except for the blank group, the other groups adopted the method of "environmental factors + fat and sweet diet + biological factors" to prepare the rat model of damp heat syndrome of febrile diseases. After modeling, they were administered by gavage for 7 days. During the experiment, the general state, body weight and body temperature were observed, the gastric residue rate of rats was calculated by weighing method, the intestinal propulsion rate of rats was calculated by charcoal propulsion method, and the levels of serum motilin (MTL), gastrin (GAS), somatostatin (SS), substance P (SP),IL-4 and interferon-γ (IFN-γ) were detected by ELISA, and the changes of aquaporin 3 (AQP3) mRNA transcription level were detected by real-time PCR.Results:Compared with the model group, the weight of rats in Guiling Gao high dose group increased after experiment of 22 days ( P<0.05), and body temperature of rats in Guiling Gao medium and high dose group decreased in 19-20 day ( P<0.01); and the gastric emptying rate and the small intestine propulsion rate of small intestine in Guiling Gao medium and high dose group increased significantly ( P<0.01 or P<0.05); the serum MTL, GAS and SP levels increased ( P<0.01 or P<0.05), and SS decreased ( P<0.01 or P<0.05) in the Guiling Gao medium and high dose groups; The levels of IL-4, IFN-γ and IFN-γ/IL-4 ratio decreased ( P<0.01); The expression of AQP3 mRNA (1.16 ± 0.25 vs. 0.23 ± 0.01) in the Guiling Gao high dose group was up-regulated ( P<0.01). Conclusions:Guiling Gao can effectively improve the activity state of damp-heat syndrome model rats caused by complex factors. This mechanism may be related to enhancing gastrointestinal movement, increasing gastrointestinal hormone secretion, restoring the dynamic balance of immune system Th1/Th2 and promoting the transport of water from intestinal cavity.

Objective:To investigate the influences of age-adjusted Charlson comorbidity index (ACCI) on prognosis of patients undergoing laparoscopic radical gastrectomy.Methods:The retrospective cohort study was conducted. The clinicopathological data of 242 gastric cancer patients who underwent laparoscopic radical gastrectomy in 19 hospitals of the Chinese Laparoscopic Gastrointestinal Surgery Study Group-04 study, including 54 patients in Fujian Medical University Union Hospital, 32 patients in the First Hospital of Putian City, 32 patients in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 31 patients in Zhangzhou Affiliated Hospital of Fujian Medical University, 17 patients in Nanfang Hospital of Southern Medical University, 11 patients in the First Affiliated Hospital with Nanjing Medical University, 8 patients in Qinghai University Affiliated Hospital, 8 patients in Meizhou People′s Hospital, 7 patients in Fujian Provincial Hospital, 6 patients in Zhongshan Hospital of Fudan University, 6 patients in Longyan First Hospital, 5 patients in the First Affiliated Hospital of Xinjiang Medical University, 5 patients in the First Hospital Affiliated to Army Medical University, 4 patients in the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, 4 patients in West China Hospital of Sichuan University, 4 patients in Beijing University Cancer Hospital, 3 patients in the First Affiliated Hospital of Xiamen University, 3 patients in Guangdong Provincial People′s Hospital, 2 patients in the First Affiliated Hospital of Xi′an Jiaotong University, from September 2016 to October 2017 were collected. There were 193 males and 49 females, aged 62(range, 23?74)years. Observation indicators: (1) age distribution, comorbidities and ACCI status of patients; (2) the grouping of ACCI and comparison of clinicopathological characteristics of patients in each group; (3) incidence of postoperative early complications and analysis of factors affecting postoperative early complications; (4) follow-up; (5) analysis of factors affecting the 3-year recurrence-free survival rate of patients. Follow-up was conducted using outpatient examination or telephone interview to detect postoperative survival of patients up to December 2020. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(range), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test or Fisher exact probability. Comparison of ordinal data was conducted using the nonparametric rank sum test. The X-Tile software (version 3.6.1) was used to analyze the best ACCI grouping threshold. The Kaplan-Meier method was used to calculate survival rates and draw survival curves. The Log-Rank test was used for survival analysis. The Logistic regression model was used to analyze the factors affecting postoperative early complications. The COX proportional hazard model was used for univariate and multivariate analyses of factors affecting the 3-year recurrence-free survival rate of patients. Multivariate analysis used stepwise regression to include variables with P<0.05 in univariate analysis and variables clinically closely related to prognosis. Results:(1) Age distribution, comor-bidities and ACCI status of patients. Of the 242 patients, there were 28 cases with age <50 years, 68 cases with age of 50 to 59 years, 113 cases with age of 60 to 69 years, 33 cases with age of 70 to 79 years. There was 1 patient combined with mild liver disease, 1 patient combined with diabetes of end-organ damage, 2 patients combined with peripheral vascular diseases, 2 patients combined with peptic ulcer, 6 patients combined with congestive heart failure, 8 patients combined with chronic pulmonary diseases, 9 patients with diabetes without end-organ damage. The ACCI of 242 patients was 2 (range, 0-4). (2) The grouping of ACCI and comparison of clinicopathological characteristics of patients in each group. Results of X-Tile software analysis showed that ACCI=3 was the best grouping threshold. Of the 242 patients, 194 cases with ACCI <3 were set as the low ACCI group and 48 cases with ACCI ≥3 were set as the high ACCI group, respectively. Age, body mass index, cases with preoperative comorbidities, cases of American Society of Anesthesiologists classification as stage Ⅰ, stage Ⅱ, stage Ⅲ, tumor diameter, cases with tumor histological type as signet ring cell or poorly differentiated adenocarcinoma and cases with tumor type as moderately or well differentiated adenocarcinoma, cases with tumor pathological T staging as stage T1, stage T2, stage T3, stage T4, chemotherapy cycles were (58±9)years, (22.6±2.9)kg/m 2, 31, 106, 85, 3, (4.0±1.9)cm, 104, 90, 16, 29, 72, 77, 6(4,6) in the low ACCI group, versus (70±4) years, (21.7±2.7)kg/m 2, 23, 14, 33, 1, (5.4±3.1)cm, 36, 12, 3, 4, 13, 28, 4(2,5) in the high ACCI group, showing significant differences in the above indicators between the two groups ( t=-14.37, 1.98, χ2=22.64, Z=-3.11, t=-2.91, χ2=7.22, Z=-2.21, -3.61, P<0.05). (3) Incidence of postoperative early complications and analysis of factors affecting postoperative early complications. Of the 242 patients, 33 cases had postoperative early complications, including 20 cases with local complications and 16 cases with systemic complica-tions. Some patients had multiple complications at the same time. Of the 20 patients with local complications, 12 cases had abdominal infection, 7 cases had anastomotic leakage, 2 cases had incision infection, 2 cases had abdominal hemorrhage, 2 cases had anastomotic hemorrhage and 1 case had lymphatic leakage. Of the 16 patients with systemic complications, 11 cases had pulmonary infection, 2 cases had arrhythmias, 2 cases had sepsis, 1 case had liver failure, 1 case had renal failure, 1 case had pulmonary embolism, 1 case had deep vein thrombosis, 1 case had urinary infection and 1 case had urine retention. Of the 33 cases with postoperative early complications, there were 3 cases with grade Ⅰ complications, 22 cases with grade Ⅱ complications, 5 cases with grade Ⅲa complications, 2 cases with grade Ⅲb complications and 1 case with grade Ⅳ complica-tions of Clavien-Dindo classification. Cases with postoperative early complications, cases with local complications, cases with systemic complications were 22, 13, 9 in the low ACCI group, versus 11, 7, 7 in the high ACCI group, respectively. There were significant differences in cases with postoperative early complications and cases with systemic complications between the two groups ( χ2=4.38, 4.66, P<0.05), and there was no significant difference in cases with local complications between the two groups ( χ2=2.20, P>0.05). Results of Logistic regression analysis showed that ACCI was a related factor for postoperative early complications of gastric cancer patients undergoing laparoscopic radical gastrectomy [ odds ratio=2.32, 95% confidence interval ( CI) as 1.04-5.21, P<0.05]. (4) Follow-up. All the 242 patients were followed up for 36(range,1?46)months. During the follow-up, 53 patients died and 13 patients survived with tumor. The 3-year recurrence-free survival rate of the 242 patients was 73.5%. The follow-up time, cases died and cases survived with tumor during follow-up, the 3-year recurrence-free survival rate were 36(range, 2-46)months, 29, 10, 80.0% for the low ACCI group, versus 35(range, 1-42)months, 24, 3, 47.4% for the high ACCI group. There was a significant difference in the 3-year recurrence-free survival rate between the two groups ( χ2=30.49, P<0.05). (5) Analysis of factors affecting the 3-year recurrence-free survival rate of patients. Results of univariate analysis showed that preoperative comorbidities, ACCI, tumor diameter, histological type, vascular invasion, lymphatic invasion, neural invasion, tumor pathological TNM staging, postoperative early complications were related factors for postoperative 3-year recurrence-free survival rate of gastric cancer patients undergoing laparoscopic radical gastrectomy [ hazard ratio ( HR)=2.52, 3.64, 2.62, 0.47, 2.87, 1.90, 1.86, 21.77, 1.97, 95% CI as 1.52-4.17, 2.22-5.95, 1.54-4.46, 0.27-0.80, 1.76-4.70, 1.15-3.12, 1.10-3.14, 3.01-157.52, 1.11-3.50, P<0.05]. Results of multivariate analysis showed that ACCI, tumor pathological TNM staging, adjuvant chemotherapy were indepen-dent influencing factors for postoperative 3-year recurrence-free survival rate of gastric cancer patients undergoing laparoscopic radical gastrectomy ( HR=3.65, 11.00, 40.66, 0.39, 95% CI as 2.21-6.02, 1.40-86.73, 5.41-305.69, 0.22-0.68, P<0.05). Conclusions:ACCI is a related factor for post-operative early complications of gastric cancer patients undergoing laparos-copic radical gastrectomy. ACCI, tumor pathological TNM staging, adjuvant chemotherapy are indepen-dent influencing factors for postoperative 3-year recurrence-free survival rate of gastric cancer patients undergoing laparoscopic radical gastrectomy.

Objective To observe the therapeutic effect of oral use of Yibai Tongfeng Pills for the treatment ofgouty arthritis with damp-heat obstruction. Methods One hundred and sixteen gouty arthritis patients were randomized into treatment group (N = 62) and control group (N = 54). The treatment group was treated with Yibai Tongfeng Pills orally, and the control group was treated with oral use of Colchicine Tablets and Sodium Bicarbonate Tablets at acute stage and with oral use of Benzbromarone Tablets at remission stage. Twelve weeks constituted one treatment course. Clinical efficacy of the two groups was evaluated after treatment, and the changes of C-reactive protein(CRP), white blood cell(WBC) and uric acid(UA) levels in the blood of the two groups were observed before and after treatment. Results (1) The total effective rate of the treatment group was 93.55%and that of the control group was 83.33%, the difference being significant(P<0.05).(2) After treatment, the scores of syndrome manifestations of the two groups were obviously decreased(P < 0.05 compared with those before treatment), and the decrease in the treatment group was superior to that in the control group(P<0.05) . (3) After treatment, CRP, WBC and UA levels in the blood of the two groups were much improved(P < 0.05 compared with those before treatment), and the improvement of CRP in the treatment group was superior to that in the control group(P<0.05), while the differences of the improvement of WBC and UA between the two groups were insignificant (P > 0.05). Conclusion Yibai Tongfeng Pills are effective for the treatment of gouty arthritis with damp-heat obstruction by improving syndrome manifestations and rapidly decreasing CRP level.

Objective To study computer toxicity prediction technology and predict the acute toxicity of Chinese materia medica; To provide a new way and method for safety evaluation of traditional Chinese medicine. Methods First, Mold2 software (version 2.0.0) was used to calculate molecular descriptors of 7409 chemical components. After preliminary screening of molecular descriptors, quantitative structure-activity relationship (QSAR) models were built up with Random Forest (RF) for screening the optimum prediction model. From the 83 kinds of toxic Chinese materia medica in Chinese Pharmacopoeia (2010 edition), acute toxicity of 60 kinds of Chinese materia medica reported from monomer structure (1692 chemical components) were under prediction.Results Totally 7409 pieces of data were obtained. When the descriptors were 52, RF modeling accuracy and Kappa were the highest, 0.712 and 0.436 respectively. Compound clusters were divided into 3 types according to optimum molecule descriptors (52). The accuracy and Kappa of the optimum model for the first type of compounds were 0.666 and 0.476 respectively; the accuracy and Kappa of the optimum model for the second type of compounds were 0.804 and 0.381 respectively; the accuracy and Kappa of the optimum model for the third type of compounds were 0.709 and 0.373 respectively. It was predicted that 60 kinds of Chinese materia medica containing 0 violent toxic compound, 2 high toxic compounds, 172 medium toxic compounds and 1518 low toxic compound.Conclusion QSAR model for prediction study on acute toxicity of chemical components of Chinese mareria medica can provide references combination medication and experimental studies.

In order to provide a new way and method for safety evaluation of Chinese materia medica (CMM) and also to provide a reference for conventional animal experiments, computer toxicity prediction technique and method were established to predict the cardiotoxicity of CMM. Mold2 software (version 2.0.0) was used to calculate molecular descriptors of 1034 chemical components. Then, the random forest (RF) method and the support vector machine (SVM) method were used to screen the descriptors. After that, boosting trees method, SVM, regularized discriminant analysis method and RF method were used to build up prediction model, respectively. Finally, the cardiotoxicity of chemical components was predicted by the quantitative structure-activity relationship (QSAR) model with the best accuracy and Kappa value. The results showed that by comparing the accuracy and Kappa value of prediction model, it was found that the RF model was the optimal algorithm model with 86.3%accuracy and the Kappa value of 0. 725. Through the prediction research on chemical components of Chinese herbs with toxicity recorded in the Pharmacopoeia of People’s Republic of China (version2010),suchasEvodia rutaecarpa,North bean root,Murraya incense,some meaningful results had been received. It was concluded that QSAR model on prediction research of chemical components of Chinese herbs provided important references for further experimental studies and clinical researches.