"Toxicity Testing in the 21st Century—A Vision and Strategy"proposed by the National Research Council of US has brought innovative directives and objectives for toxicity evaluation and risk assessment,pushing forward the next generation of toxicity testing and risk assessment.In this initiative,the concept of adverse outcome pathways(AOPs)has emerged as a prominent methodology,capturing the attention of toxicologists and researchers due to its promising applications in recent years.The quantitative AOP(qAOP)is an extension of the adverse outcome pathway,which is built upon the foundational qualitative adverse outcome pathway model and leverages mathematical frame-works to depict dose-response and/or response-response relationships.This article reviews the princi-ples and advancement surrounding qAOP,introduceds two prevalent methodologies for constructing qAOP,Bayesian network models and regression models,and demonstrates diverse applications of qAOP.Actual cases are used to underscore the transformative role of qAOP in contemporary toxicology and risk assessment practices.

Zhuye Shigaotang， first recorded in ZHANG Zhongjing's Synopsis of the Golden Chamber （《金匮要略》）， is a commonly used prescription for treating heat syndrome in modern times. However， physicians of the past dynasties have different opinions on the mechanism of Zhuye Shigaotang in disease treatment. Based on HUANG Yuanyu's theory of Qi circulation， this paper holds that the root cause of the diseases treated by Zhuye Shigaotang is the deficiency of spleen and stomach in the middle energizer and the dysfunction of ascending and descending. The failure of Yin ascending leads to the failure of Yang transformation， and the failure of Yang descending causes the failure of Yin generation. As a result， heat and fire become predominant in the heart， lung， and stomach， which causes Qi counterflow and fluid consumption. Based on this pathogenesis， Zhuye Shigaotang is mainly composed of pungent， warm， sweet， and cold herbs. The combination of these herbs can protect the spleen and stomach and recover the Qi movement in the middle energizer， thereby clearing heat and fire， descending Qi， and promoting the generation of Qi and fluid. In clinical practice， this prescription can be applied to treating the syndromes of deficiency in spleen and stomach， dysfunction of middle energizer in transportation， dysfunction of ascending and descending， excessive heat and fire， and Qi counterflow and fluid consumption. The interpretation of Zhuye Shigaotang from the theory of Qi circulation can provide a new idea for differentiating syndromes， seeking causes， and developing prescriptions， which broadens the scope of clinical application of this prescription and provides a reference for interpreting ZHANG Zhongjing's method of compatibility.

Objective:To investigate the kinetic metrics of 68Ga-fibroblast activation protein inhibitor (FAPI)-04 in pancreatic cancers and normal organs by using total-body PET dynamic imaging. Methods:From December 2020 to December 2021, 68Ga-FAPI-04 total-body PET/CT dynamic imaging were performed on 6 pancreatic cancer patients (3 males, 3 females, median age 55.5 years) in Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. Images were respectively analyzed. Manual delineations of volume of interests (VOIs) on multiple normal organs and pathological lesions were performed and time-to-activity curves (TACs) were generated. A reversible two-tissue compartment model (2TCM) was fitted for each tissue TAC. Rate constants including K1, k2, k3 and k4, and the total volume of distribution ( Vt) were obtained and compared by tissue types. Wilcoxon rank sum test and Spearman correlation analysis were used for data analysis. Results:Kinetic metrics varied significantly among normal organs and pancreatic cancer lesions ( z values: 2.00-1 240.00, all P<0.05). The highest K1 among lesions was observed in primary tumor (0.30 min -1), which was observed in the spleen (1.42 min -1) among normal organs. The highest k2 among lesions was observed in peritoneal metastases (0.24 min -1), which was observed in the spleen (2.59 min -1) among normal organs. Primary tumor showed the highest k3 of 0.17 min -1 among lesions, and the pancreas had the highest k3 of 0.16 min -1 among normal organs. Primary tumor had the highest k4 of 0.03 min -1 among lesions, and the heart, lungs, parotid glands had high k4(0.06 min -1) among normal organs. Vt were higher in pathological lesions compared to normal organs, with the highest in primary tumor (13.78 ml/cm 3). There were correlations between Vt in lesions and SUV mean( rs=0.86, P<0.001) or SUV max ( rs=0.77, P<0.001). Conclusion:The rate constants including K1, k2, k3 and k4, and Vt of 68Ga-FAPI-04 vary among normal organs and lesions.

Objective To investigate the clinical characteristics of gastrointestinal involvement in polyarteritis nodosa (PAN),and to improve the understanding of the disease.Methods PAN patients hospitalized in Peking Union Medical College Hospital from March 2002 to September 2016 were enrolled in this study,and were divided into gastrointestinal involvement group and non-gastrointestinal involvement group according to clinical manifestations and imaging findings.Data on clinical features,treatments and outcome were recorded.t test,chi-square test were used for statistical analysis.Results A total of 117 patients with PAN were hospitalized in the past 14 years.The prevalence of gastrointestinal involvement was 38％(44 cases).There was no significant difference in age and sex between the two groups (P＞0.05).Abdominal pain (29 cases,66％) was the most frequent manifestation,then gastrointestinal bleeding (10 cases,23％),splenic infarction (3 cases,7％),gastrointestinal ulcers (2 cases,5％),intestinal obstruction or diarrhea (each 2 cases,5％),and vomiting (1 case,2％).Patients with gastrointestinal involvement had more frequent fatigue (27％ vs 11％;x2=5.156,P=0.023),increased diastolic pressure (55％ vs 34％;x2=4.647,P=0.031),renal (34％ vs 18％;x2=3.998,P=0.046) and cardiac (25％ vs 8％;x2=6.225,P=0.013) involvements.ESR in the gastrointestinal involvement group was significantly higher (75％ vs 56％;x2=4.190,P=0.041).The average follow-up time was 315.8 (20.3,441.3) days,the relapse rate was higher in the gastrointestinal involvement group (23％ vs 8％;x2=4.895,P=0.027).The incidence of death or the irreversible organ injury was higher in the gastrointestinal involvement group (27％ vs 11％,x2=5.156,P=0.023).Conclusion Gastrointestinal invol-vement in poly-arteritis nodosa is common and its condition is severe.The incidence of relapse and death or irreversible organ injury is high.

Objective To investigate the clinical characteristics of polyarteritis nodosa (PAN) patients with renal involvement. Methods PAN patients admitted to the department of rheumatology, department of pediatrics, department of nephrology, general internal medicine department and department of vascular surgery at Peking Union Medical College Hospital from June 2012 to August 2018 were enrolled in this study and were divided into two groups according to renal involvement or not. The clinical characteristics were analyzed. Results A total of 94 PAN patients were finally enrolled and 57 (60.64%) presented kidney manifestation. The mean age of onset was (37.76±17.40) years old and the interval from onset to diagnosis was 10 (0 to 240) months. Forty patients were misdiagnosed once or more times. In patients with renal involvement, 9 cases suffered from renal ischemia or infarction, 31 with microscopic haematuria, 26 with proteinuria, renal artery or its branch involved in 17 cases, renal vein thrombosis in 1 case, 4 cases with pyeloureterectasis, one case with renal fascia thickening, 33 cases with impaired renal function (serum creatinine>84 μmol/L) including creatinine>140 μmol/L in 10 patients. Renal artery branch stenosis was the most common presentation [9 cases (52.94%)] of renal vascular involvement, other abnormalities including nodular dilatation [4 cases (23.53%)], occlusion [3 cases (17.65%)]. There were significant differences (P<0.05) in the PAN patients with and without renal involvement in the following: age of onset [(33.72±16.13) years vs. (43.97±17.66)years, t2=2.901, P=0.005], weight loss(≥4kg since PAN onset) [25(43.86%) vs. 7(18.92%), χ2=6.216, P=0.013], elevation of diastolic blood pressure [22(38.60%) vs. 7 (18.92%), χ2=4.072, P=0.044], acromegaly gangrene [18(31.58%) vs. 21(56.76%), χ2=5.859, P=0.015], and gastrointestinal artery involvement [20(35.09%) vs. 6(1.22%), χ2=3.993, P=0.046]. Laboratory parameters and the application of glucocorticoid and cyclophosphamide therapies were similar in two groups (all P>0.05). Conclusion Young PAN patients are more likely to be associated with renal involvement, especially gastrointestinal arteries.

Objective: To investigate the clinical characteristics of polyarteritis nodosa (PAN) patients with renal involvement. Methods: PAN patients admitted to the department of rheumatology, department of pediatrics, department of nephrology, general internal medicine department and department of vascular surgery at Peking Union Medical College Hospital from June 2012 to August 2018 were enrolled in this study and were divided into two groups according to renal involvement or not. The clinical characteristics were analyzed. Results: A total of 94 PAN patients were finally enrolled and 57 (60.64%) presented kidney manifestation. The mean age of onset was (37.76±17.40) years old and the interval from onset to diagnosis was 10 (0 to 240) months. Forty patients were misdiagnosed once or more times. In patients with renal involvement, 9 cases suffered from renal ischemia or infarction, 31 with microscopic haematuria, 26 with proteinuria, renal artery or its branch involved in 17 cases, renal vein thrombosis in 1 case, 4 cases with pyeloureterectasis, one case with renal fascia thickening, 33 cases with impaired renal function (serum creatinine>84 μmol/L) including creatinine>140 μmol/L in 10 patients. Renal artery branch stenosis was the most common presentation [9 cases (52.94%)] of renal vascular involvement, other abnormalities including nodular dilatation [4 cases (23.53%)], occlusion [3 cases (17.65%)]. There were significant differences (P<0.05) in the PAN patients with and without renal involvement in the following: age of onset [(33.72±16.13) years vs. (43.97±17.66) years, t²=2.901, P=0.005], weight loss(≥4kg since PAN onset) [25(43.86%) vs. 7(18.92%), χ²=6.216, P=0.013], elevation of diastolic blood pressure [22(38.60%) vs. 7(18.92%), χ²=4.072, P=0.044], acromegaly gangrene [18(31.58%) vs. 21(56.76%), χ²=5.859, P=0.015], and gastrointestinal artery involvement [20(35.09%) vs. 6(1.22%), χ²=3.993, P=0.046]. Laboratory parameters and the application of glucocorticoid and cyclophosphamide therapies were similar in two groups (all P>0.05). Conclusion Young PAN patients are more likely to be associated with renal involvement, especially gastrointestinal arteries.

Objective: To investigate the etiology, clinical and pathological characteristics of laryngeal leukoplakia and the predictive risk factors of recurrence and malignant transformation. Methods: Clinical data of 263 patients with laryngeal leukoplakia between January 2000 and December 2015 were analyzed retrospectively. Results: The pathological diagnoses included squamous epithelial hyperplasia (54.4%), mild dysplasia (17.9%), moderate dysplasia (12.2%), severe dysplasia and carcinoma in situ (12.5%), and invasive carcinoma (3.0%). Age and the extent of lesion were statistically different among different pathological groups (P<0.05). Gender, smoking and alcohol consumption did not show statistical differences among different pathological groups (P>0.05). Follow-up of 215 patients, excluding 6 cases of invasive carcinoma. The recurrence rate was 20.6%(43/209), and the malignant transformation rate was 5.3%(11/209). Multivariate analysis showed that pathological classification of moderate to severe dysplasia was the independent risk factor for recurrence and malignant transformation of laryngeal leukoplakia (P<0.05). In patients with severe dysplasia and carcinoma in situ, the recurrence proportion of conservative treatment, vocal cords (partial) resection and radiotherapy were 8/10, 0/10 and 2/11 respectively. Conclusions Laryngeal leukoplakia occurs frequently in elderly men with long-term smoking history. Pathological diagnoses are different. The grade of dysplasia is the predictive risk factor for the recurrence and malignant transformation of laryngeal leukoplakia. More aggressive treatment and closer follow-up should be warranted for patients with moderate dysplasia, severe dysplasia and carcinoma in situ.

Objective: To introduce the method of transoral coblation-assisted endoscopic minimally invasive surgery for superficial tongue base tumour. Methods: A total of 15 patients treated with transoral coblation-assisted endoscopic minimally invasive surgery from Mar. 2006 to Aug. 2016 were retrospectively reviewed. There were 9 patients with malignant tumors, 6 patients with benign neoplasms. Adjuvant postoperative radiation therapy was applied in three cases of squamous cell carcinoma, neck was performed in four cases of cancer. One case of non-Hodgkin lymphoma received postoperative chemotherapy. Results: One case with ectopic thyroid gland was treated by subtotal resection and one case with squamous cell carcinoma changed into open surgery because of major lingual artery bleeding. The En bloc resection under edoscope was achieved in 92.86%(13/14)of patients. Fifteen cases of neoplasms were followed-up for 8-50 months(median 20 months), one patient with Cowden syndrome was lost to follow-up because of appendical carcinoid combined pulmonary metastasis, one patient with non-Hodgkin lymphoma died of recurrence in other head neck areas 2 years after chemotherapy. Conclusion Transoral coblation-assisted endoscopic surgery can successfully treat for the patients with superficial tongue base tumours.

Objective: To explore the safety and validity of endoscopic cricopharyngeal myotomy in patients with cricopharyngeal achalasia. Methods: A total of 19 patients with cricopharyngeal achalasia suffered from sustained dysphagia were enrolled in this study. The patients were divided into transcervical cricopharyngeal myotomy(CPM) group and endoscopic CPM (ECPM) group. Swallowing function and complications were evaluated.SPSS7.0 software was used to analyze the data. Results: The swallowing function improved significantly in seven patients in ECPM group, and 9 patients improved in CPM group.The video fluoroscopic swallowing study(VFSS)-swallowing score, VFSS-aspiration score and drinking test score were (3.1±1.1), (3.4±0.8) and (2.0±0.6)in post-ECPM, (3.4±1.4), (3.0±0.9) and (2.2±0.6)in post-CPM. No statistical difference was found in validity between CPM group and ECPM group(t=-0.435, t=1.086, t=-0.607, P>0.05). No statistical difference was observed on the occurrence of complication between two groups. Only one patient had subcutaneous emphysema after operation in ECPM. Conclusions New surgical instruments and endoscopic surgical technique were safe and effective for cricopharyngeal achalasia. Because these instruments are cheaper, laryngeal endoscopic cricopharyngeal myotomy is easier to be popularized more easily than microscopic laser assistted CPM.

A novel series of sorafenib analogs containing 2-picolinyl hydrazide moiety were designed and synthesized. In vitro, most of synthesized compounds have antiproliferation activity on MDA-MB-231, ACHN, HepG2, Mia-PaCa-2 and SW1990 cell lines tested by MTT assay. It is worth noting that the antitumor activities of compounds 2c, 2d and 2f are more potent than that of sorafenib on pancreatic cancer cells Mia-PaCa-2 and SW1990, and the activities of compounds 3f and 3g are 2-3 times than that of sorafenib on human hepatocellular carcinoma HepG2 cell line.