[摘 要] 目的：评估放疗作为原位疫苗的联合治疗模式在晚期软组织肉瘤（STS）患者中的有效性和安全性。方法：回顾性分析2020年12月至2024年9月期间在南京大学医学院附属鼓楼医院肿瘤中心接受联合治疗模式的12例晚期STS患者的临床资料。12例患者均接受了联合治疗。放疗主要以大分割为主。靶向治疗：安罗替尼10例、阿帕替尼2例。免疫治疗以PD-1抗体为主。主要研究终点为疾病控制率（DCR），次要研究终点为客观有效率（ORR）及安全性。结果：接受联合治疗的12例STS患者中有0例CR，4例PR，7例SD，1例PD。ORR为33%，DCR为91.7%，其中靶病灶的DCR为100%。12例患者中，9例出现Ⅰ~Ⅱ级不良反应。最常发生的血液学不良反应是贫血（6例）、肝功能检查结果异常（3例）。最常发生的非血液学不良反应是尿蛋白（5例）、高血压（4例）、甲状腺功能异常（3例）、厌食（3例）、恶心呕吐（2例）；仅2例发生Ⅲ级血液毒性，有1例发生Ⅲ级气胸。结论：放疗作为原位疫苗的联合治疗模式在晚期STS患者中展现出较高的DCR，且未出现严重不良反应。该联合治疗模式具有良好的有效性与安全性。

ObjectiveTo explore the potential mechanism of Dingchuan Granule （定喘颗粒， DG） in the treatment of respiratory syncytial virus （RSV） pneumonia. MethodsA total of 60 male Sprague Dawley （SD） rats were randomly divided into control group， model group， ribavirin group， DG low-dose group， DG middle-dose group， and DG high-dose group， with 10 rats in each group. Except for the control group， rats were administrated with RSV via intranasal drip. After model establishment， the DG low-， middle-， and high-dose groups were administrated via oral gavage with DG at 3.47， 6.93， and 13.86 g/（kg·d） respectively， while the ribavirin group was administrated via oral gavage with ribavirin at 15.75 mg/（kg·d）. The drug was given once daily for one week. The rats in the control group and the model group were not given any drug， only subjected to the grasping action. Twenty-four hours after the last administration， the pathological changes of lung tissues were observed and scored using HE staining. The levels of serum inflammatory factors， including tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-6 （IL-6）， were detected by colorimetry. The protein levels of nuclear factor （erythroid derived 2）-like 2 （Nrf2）， Kelch-like ECH-associated protein 1 （Keap1）， heme oxygenase 1 （HO-1）， and NAD（P）H quinone dehydrogenase 1 （NQO1） in lung tissues were measured by Western Blot. The RSV load as well as the gene expression levels of Nrf2， Keap1， HO-1， and NQO1 in lung tissues were determined by qRT-PCR. The level of reactive oxygen species （ROS） in rat lung tissues was detected using chemiluminescence. The levels of glutathione （GSH） and malondialdehyde （MDA） in rat lung tissues were measured by a microassay. ResultsCompared with the control group， other groups had significant increases in pathological score of lung tissue， RSV load， levels of ROS， MDA， serum TNF-α， IL-1β， and IL-6； decrease in GSH level， increases in expression level of Keap1 protein and its mRNA in lung tissue， and significant decrease in levels of Nrf2， HO-1， expression level of NQO1 protein and its mRNA （P＜0.05）. Compared with the model group， all the above-mentioned indicators in the DG low-， middle-， and high-dose groups and the ribavirin group were improved to varying degree （P＜0.05）. The levels of serum TNF-α， IL-1β， and IL-6 in rats of DG dose groups showed a dose-dependent pattern， the DG high-dose group exhibiting the best effect （P＜0.05）. The DG high-dose group was superior to the DG low- and middle-dose groups in reducing the levels of ROS and MDA， and increasing the level of GSH in lung tissues （P＜0.05）. The DG high-dose group and the ribavirin group had better effect than the DG middle-dose group in reducing the RSV load （P＜0.05）. The DG high-dose group was superior to the ribavirin group in improving the protein levels of Nrf2， Keap1， HO-1， and NQO1 （P＜0.05）. ConclusionDG could inhibit oxidative stress by regulating the Nrf2/Keap1/HO-1/NQO1 signaling pathway to improve pulmonary inflammation and treat RSV pneumonia， with the DG high-dose group showing the best effect.

The "pre-disease" theory of traditional Chinese medicine focuses on the dynamic and continuous evolution from health to disease, and emphasizes early identification and intervention in the complex and gradual process of evolution from health to disease. The "pre-disease" theory and complexity science share the same perspective on health and disease from the standpoint of features of the dynamic evolution and holism, i. e., life is considered as a complex system with ongoing dynamic changes, which exhibit the nonlinear features of " homeostasis-destabilization-phase transition-another homeostasis". In this paper, from the perspective of nonlinear dynamics in complexity science, we explain the scientific connotation of the evolution law of "pre-disease"-disease based on the theory of critical slowing down in traditional Chinese medicine. Based on the theory of critical slowing down and the dynamic network biomarker method generated by its development, combined with the macro signs of comprehensive analysis of data gained by four diagnostic method and the micro features including transcriptomics and the microbiomics, this paper proposes to integrate macro and micro multi-hierarchy information to construct a "pre-disease" critical slowing down identification model with the characteristics of traditional Chinese medicine diagnosis and treatment, which provides a new perspective and method for the early warning of complex diseases.

Objective To investigate the expression of Nanog and its regulatory relationship with MMP-2/MMP-9 proteins in esophageal squamous cell carcinoma(ESCC).Methods We detected Nanog and MMP-2/MMP-9 protein expressions in 127 ESCC tissues and 82 adjacent normal tissues using immunohistochemistry and explored their correlations with the clinicopathological parameters and prognosis of the patients.GEO database was utilized to analyze the pathways enriched with the stemness-related molecules including Nanog,and TIMER online tool was used to analyze the correlations among TβR1,MMP-2,and MMP-9 in esophageal cancer.Results Nanog and MMP-2/MMP-9 proteins were significantly upregulated in ESCC tissues and positively intercorrelated.Their expression levels were closely correlated with infiltration depth and lymph node metastasis of ESCC but not with age,gender,or tumor differentiation.The patients with high expressions of Nanog and MMP-2/MMP-9 had significantly shorter survival time.Bioinformatics analysis showed enrichment of stemness-associated molecules in the TGF-β signaling pathway,and the expressions of MMP-2/MMP-9 and TβR1 were positively correlated.In cultured ESCC cells,Nanog knockdown significantly decreased the expression of TβR1,p-Smad2/3,MMP-2,and MMP-9 and strongly inhibited cell migration.Conclusion The high expressions of Nanog,MMP-2,and MMP-9,which are positively correlated,are closely related with invasion depth,lymph node metastasis,and prognosis of ESCC.Nanog regulates the expressions of MMP-2/MMP-9 proteins through the TGF-β signaling pathway,and its high expression promotes migration of ESCC cells.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Objective To evaluate the effect of para-esophageal and para-gastric vessels(PEPGV)on endoscopic secondary prophylaxis for varices.Methods The clinical data of patients with cirrhosis-related esophagogastric varices(EGV)who underwent endoscopic variceal ligation and/or obliteration,and had hepatic venous pressure gradient(HVPG)result between January 2020 and December 2020 in Zhongshan Hospital,Fudan University were retrospectively analyzed.Patients were divided into a group without PEPGV and a group with PEPGV based on CT imaging of the portal vein.The main outcome was 2-year re-bleeding.Results A total of 69 patients were included,and 27 of them had PEPGV.There was no statistical difference in baseline characteristics,blood indexes(included hemoglobin level,prothrombin time and albumin level),HVPG,and the secondary prophylactic endoscopic treatment ways between the two groups.A total of 25 patients experienced re-bleeding within 2 years after endoscopic treatment,including 15 in the group with PEPGV and 10 in the group without PEPGV.Kaplan-Meier analysis showed that the cumulative 2-year re-bleeding rate was significantly higher in the group with PEPGV than in the group without PEPGV(60.07％vs 32.79％,P=0.022).Further multivariate Cox analysis showed that PEPGV was an independent predictor of re-bleeding after endoscopic treatment in EGV patients(HR=2.33,95％CI 1.01-5.39,P=0.047).Conclusions The PEPGV is an independent predictor of re-bleeding after endoscopic treatment in EGV patients.It is suggested that when patients with EGV receive endoscopic treatment to prevent re-bleeding,portal vascular CT is suggested to evaluate PEPGV.For patients with giant extraluminal vascular masses,fully evaluating other treatment options such as transjugular intrahepatic portosystemic shunt,or adjusting endoscopic treatment ways is recommended.

Objective To explore the effects of anticoagulation treatment to postoperative bleeding events in liver cirrhosis patients with gastric varices and portal vein thrombosis.Methods Patients diagnosed with portal vein thrombosis and treated with endoscopic cyanoacrylate injection at Zhongshan Hospital,Fudan University due to gastric variceal bleeding from January 2023 to December 2023 were included.Clinical data of patients were collected,and patients were divided into anticoagulant group and non-anticoagulant group based on whether anticoagulant treatment was performed within 48 h after treatment.Re-bleeding in patients was evaluated in 6 weeks of follow-up.Cox regression was used for univariate and multivariate analysis of re-bleeding within 6 weeks after treatment.Results A total of 160 patients were included,of whom 65 patients received anticoagulation treatment within 48 h after endoscopic cyanoacrylate injection.There were no statistically significant differences in gender,etiology of liver cirrhosis,dosage of cyanoacrylate and sclerosing agents,and Child-Pugh grading between the two groups.There was no statistically significant difference in re-bleeding rate within 6 weeks after treatment between the two groups(1.54％vs 1.05％,P=0.795).Multivariate Cox regression analysis showed that the large amount of cyanoacrylate was a risk factor for re-bleeding within 6 weeks after endoscopic treatment(HR=5.862,P=0.015).Conclusions For patients with liver cirrhosis,gastric varices,and portal vein thrombosis,who receive endoscopic cyanoacrylate injection,early anticoagulation does not increase the risk of re-bleeding after treatment,while a large amount of cyanoacrylate injection may be a risk factor for re-bleeding.However,sample should be increased to verify.

Objective To compare the efficacy and safety of endoscopic ligation treatment and endoscopic tissue glue injection for secondary prevention of gastric variceal bleeding.Methods Patients with cirrhosis and esophagogastric variceal bleeding treated with gastric variceal ligation in Zhongshan Hospital,Fudan University,from January 2017 to December 2019 were screened(ligation group).And during the same period,patients underwent endoscopic cyanoacrylate treatment were also screened(tissue glue group).59 patients were included in the two groups after propensity score matching.Univariate and multivariate Cox proportional hazard regression models were used to anslyze risk factors for re-bleeding.Kaplan-Meier curves were plotted to analyze re-bleeding rate and mortality of the two treatment groups.Results There was no statistically significant difference in the eradication rate of esophagogastric varices between the ligation group and the tissue glue group(83.05％vs 79.66％,P=0.778);the ligation group required fewer median endoscopic treatments for variceal eradication(2 vs 3,P=0.017)and a lower average dosage of cyanoacrylate(0.70 mL vs 2.67 mL,P＜0.001).Multivariate Cox regression analysis showed that portal shunt was a risk factor for esophagogastric varices re-bleeding(HR=3.14,95％CI 1.02-9.68,P=0.046),endoscopic variceal ligation was a protective factor against re-bleeding(HR=0.25,95％CI 0.08-0.71,P=0.010).Compared with endoscopic cyanoacrylate injection,endoscopic ligation treatment did not significantly increase the 2-year risk of esophagogastric variceal re-bleeding(18.69％vs 36.29％,P=0.067)or risk of death(1.69％vs 3.39％,P=1.000);patients with GOV1 type had a significantly lower risk of re-bleeding after endoscopic ligation treatment(0 vs 40.27％,P=0.012)and there was a trend towards a lower re-bleeding risk in patients with GOV2 type after endoscopic ligation treatment(13.27％vs 34.16％,P=0.056).Conclusions Endoscopic ligation treatment has higher eradication rate for esophagogastric varices,and does not increase the risk of re-bleeding,death,or other adverse events.Therefore,it can be considered an effective secondary prevention way for patients with gastric varices.

Objective:To investigate whether discontinuation of previous targeted immunotherapy increases the risk of rebleeding in patients with advanced liver cancer complicated with esophageal and gastric variceal bleeding after endoscopic treatment.Methods:A retrospective cohort study was conducted to include advanced liver cancer patients who were diagnosed with esophageal and gastric variceal bleeding through endoscopic examination and treated under endoscopy at Zhongshan Hospital, Fudan University from March 1, 2020 to March 1, 2022, due to upper gastrointestinal bleeding. We collected clinical data from patients and divided them into targeted immunotherapy group and non targeted immunotherapy group based on whether they received targeted immunotherapy before bleeding; Follow up observation was conducted for 6 months to evaluate the patient′s re bleeding and survival status.Results:A total of 55 patients were included, of which 24 had previously received targeted immunotherapy and 31 had not received targeted immunotherapy. There was no significant difference between the two groups in gender distribution, etiology, hypertension and diabetes (all P>0.05). The age of the target immunotherapy group was younger than that of the non target immunotherapy group, and the level of fibrinogen was higher than that of the non target immunotherapy group, with statistical significance ( P=0.002, 0.017). There was no statistically significant difference in the 6-month re bleeding rate (20.83% vs 22.58%, P=0.269) and 6-month mortality rate (45.83% vs 29.03%, P=0.199) between the targeted and non targeted groups of patients. Further Cox regression multivariate analysis revealed that Child-pugh grading was an independent risk factor for 6-month survival in patients with advanced liver cancer with esophageal and gastric varices ( HR=2.64, P=0.009). Conclusions:Targeted immunotherapy does not increase the rate of rebleeding in patients with advanced unresectable liver cancer after endoscopic treatment of esophageal and gastric varices. Child-pugh grading is a factor that affects the 6-month survival of advanced liver cancer patients after bleeding, and the poorer the liver function, the shorter the survival period.

Objective:To analyze the correlations between the ultrasound contrast features and the expression of human epidermal growth factor receptor 2(HER-2)of molecular biological indicators of breast cancer,and between ultrasound elastography features and that.Methods:A total of 63 patients with invasive breast cancer who admitted to The Affiliated Suzhou Hospital of Nanjing Medical University and The First Affiliated Hospital of Jiamusi University from February 2019 to June 2022 were selected as the study subjects.The HER-2 positive expression of molecular biological indicator of breast cancer was measured by immunohistochemistry.According to the immunohistochemical results,the patients were divided into positive group(22 cases)and negative group(41 cases).All patients underwent examinations of ultrasound contrast and ultrasound elastography.The differences of the features of ultrasound contrast and ultrasound elastography between the two groups were analyzed and compared.The influencing factors of HER-2 positive expression were analyzed by binary logistic regression,and the receiver operating curve(ROC)was established to assess respectively the values of single ultrasound contrast,single ultrasound elastography and the combination of them in predicting HER-2 positive expression.Results:There was significant differences in the features of ultrasound elastography between the two groups.The ratios of the irregular shape and burr at the edge of the imaging features of the patients with HER-2 positive expression were significantly higher than those of the patients with HER-2 negative expression[(86.4%vs.58.5%)and(77.3%vs.51.2%)],and the differences were statistically significant(x2=5.117,4.060,P<0.05),respectively.The difference of the features of ultrasound contrast between two groups was significant.The ratios of nourishing vessels,and the lesion enlargement≥3 cm after angiography in patients with HER-2 positive expression were significantly higher than those in the patients with HER-2 negative expression[(77.3%vs.41.5%)and(81.8%vs.39.0%)],the differences were statistically significant(x2=7.390,10.554,P<0.05),respectively.The features(shape,edge,nourishing vessels and lesion enlargement after contrast)of ultrasound contrast and ultrasound elastography were used respectively as independent variables,and the HER-2 positive expression was used as dependent variables.The logistic regression analysis showed that regular shape,smooth edge,without nourishing vessels and enlarged lesion<3 cm after angiography were protective factors for HER-2 positive expression of patients with breast cancer(OR=0.185,0.199,0.070,0.186,P<0.05),respectively.The areas under curve(AUC)values of the ROC curve of imaging features(shape,edge,nourishing vessels,and lesion enlargement after angiography)of ultrasound contrast and ultrasound elastography were respectively 0.630,0.639,0.679 and 0.714 in single predicting HER-2 positive expression of patients with breast cancer,and that of the combination of them was 0.874 in prediction.Conclusion:In features of ultrasound contrast and ultrasound elastography,the shape,edge,nourishing vessels and the enlargement lesion after contrast were the influencing factors of HER-2 positive expression in patients with breast cancer.The combined assessment of ultrasound contrast and ultrasound elastography before surgery has certain clinical reference value in predicting HER-2 expression.