Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Objective:To investigate the manpower allocation and scientific research level of radiotherapists in radiotherapy units in mainland China, aiming to provide reference for the construction of radiotherapist teams.Methods:The questionnaire was designed and produced by the organizer, released in the professional committee, professional group and other channels of the radiotherapist industry, and filled out by the technical person in charge of the radiotherapy unit through the online questionnaire survey. The collection time started from mid-May 2021 to mid-June 2021.Results:A total of 558 effective questionnaires filled out by radiotherapy units. The radiotherapy institutions participating in the survey had a total of 5500 radiotherapists, including 3702 males and 1798 females, 3754 with a bachelor's degree, 371 who are currently studying or have obtained a master's degree, 21 who are currently studying or have already obtained a doctoral degree, 3642 with junior or lower titles, 1580 with intermediate titles, and 278 with senior titles. In 2020, radiotherapists from 193 units published articles, those from 81 units received project funding, and those from 56 units obtained patent authorization, and those from 15 units had scientific research transformation. The participating units had a total of 1080 large-scale radiation therapy equipment. In 2020, the daily average number of radiotherapy patients was 47 900, the average daily load of accelerator patients was 44.35, and the average workload index per capita was 8.71. The average daily radiotherapy patients in county-level or below, city-level, and provincial-level institutions were 25.78, 65.68, and 173.76, respectively, and the per capita workload index was 5.22, 8.09, and 10.11.Conclusions:Compared with the 2019 survey, the educational background of radiotherapists in mainland China has been improved, and the title structure has been optimized to a certain extent, and the workload of large-scale radiotherapy units is larger than that of grass-roots units.

Objective:To investigate and analyze the basic occupational situation of Chinese radiotherapists and to provide references for the development and construction of the radiation therapist team in China.Methods:Between May 7, 2021 and June 15, 2021, this survey was conducted using a self-designed questionnaire, which was distributed and collected in the form of online survey to conduct a statistical analysis of the basic situation of radiotherapists in 30 provincial-level administrative regions in China.Results:A total of 2 928 valid questionnaires were collected from 30 provincial-level administrative regions. The ratio of male to female and average age of the participants were 69∶31 and 35 years (18-65), respectively. According to the survey result, 84.7% of the participants came from Tertiary A-level hospitals. In terms of educational background, the participants with doctoral, master, undergraduate, junior-college, and technical-secondary degrees accounted for 0.2%, 6.9%, 76.6%, 14.9%, and 1.4%, respectively. In terms of title, full senior technologists, associate senior technologist, technologist-in-charge, technologist, and technician in the participants accounted for 0.5%, 5.8%, 32.5%, 52.2%, and 8.2%, respectively. The participants with years of employment of 0-, 5-, 10-, 20-y accounted for 33.74%, 25.79%, 25.51%, and 14.96%, respectively. The majors of the participants included medical imaging/imaging technology (45.9%), clinical medicine (19.1%), and biomedical engineering (11.9%).Conclusions:Chinese radiotherapists tend to be younger and are rapidly increasing in number. Employers should attach importance to the career planningand continuing education of radiotherapists to improve their technical skills, in order to fully satisfy the demand for radiotherapists in the new era.

Objective:To investigate the application value of choledochoscopy in the diagnosis of cholelithiasis related diseases.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 111 patients with cholelithiasis related diseases who were admitted to the Second Affiliated Hospital of Soochow University between January 2018 and April 2019 were collected. There were 45 males and 66 females, aged (55±16)years, with the range from 20 to 89 years. The mucosal course of biliary system and the submucosal vascular density of the 111 patients were observed by choledochoscopy during operation. Observation indicators: (1) patient examinations; (2) specific case analysis. Measurement data with normal distribution were represented as Mean± SD. Count data were described as absolute numbers or percentages. Results:(1) Patient examinations: 111 patients underwent intraoperative choledochoscopy examination, and 5 patients underwent pathological examination. Five of the 111 patients had the results of intraoperative choledochoscopy examination inconsistent with results of preoperative imaging examination. (2) Specific case analysis. Case 1: the patient was diagnosed with intrahepatic and extrahepatic bile duct stones preoperatively by computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) examination. Results of intraoperative choledochoscopy examination and electronic staining under choledochoscope showed abnormal mucosa at the opening of the original cholecyst duct in the common bile duct, thickened and disordered blood vessels, which indicated the possibility of malignant transformation. Results of intraoperative rapid frozen histopathological examination showed inflammatory cell infiltration in gallbladder neck and focal glandular epithelial high-grade intraepithelial neoplasia. Results of postoperative pathological examination showed high-grade intraepithelial neoplasia of the wall of gallbladder cervical ducts, focal infiltrating myowall carcinoma and strongly positive of Cytokeratin 7 diaminobenzine staining. Case 2: results of preoperative doppler ultrasonography and MRCP showed gallbladder polyps. Intraoperative choledochoscopy examination showed gallbladder polyps with adenoma and a blood vessel at polyp root, which was diagnosed as gallbladder polyp combined with adenoma. Results of electronic staining in narrow band imaging (NBI) showed gallbladder polyps with adenoma and thick blood vessels at polyp root. Results of intraoperative rapid frozen histopathological examination showed cholesterol polyps and focal adenomatous hyperplasia. Results of postoperative pathological examination showed chronic cholecystitis with cholesterol polyps and adenomatous hyperplasia of focal glands. Case 3: results of preoperative MRCP examination showed choledocholithiasis and intrahepatic bile duct stones. Results of intraoperative choledochoscopy examination showed intrahepatic bile duct stones of large size. The patient underwent holmium laser lithotripsy and mucosal hyperplasia with soft lesion and smooth mucous epithelium was found after the stone was broken. Results of NBI and methylene electron staining showed multiple submucosal tortuous vessels in proliferative lesions behind bile duct stone. Results of intraoperative rapid frozen histopathological examination showed adenoma with high-grade intraepithelial neoplasia. Case 4: results of preoperative MRCP examination showed intrahepatic and extrahepatic bile duct stones combined with dilatation of bile duct. Results of CT examination showed multiple soft tissue density shadows of intrahepatic and extrahepatic bile ducts, which was considered as biliary papillomatosis. Results of intraoperative choledochoscopy showed small stones in the lower common bile duct and multiple segmental proliferative flocculent hyperplasia lesions on the wall of the intrahepatic and extrahepatic bile ducts. Results of electronic staining in NBI showed multiple proliferative lesions in intrahepatic and extrahepatic bile ducts and multiple curved vascular shadows under the mucosa of the lesions. Results of intraoperative rapid frozen histopathological examination showed a denomatous hyperplasia with low-grade intraepithelial neoplasia. Results of postoperative pathological examination showed adenoma with low-grade intraepithelial neoplasia. Case 5: results of preoperative magnetic resonance imaging examination showed silt-like stones in the lower part of bile duct accompanied with dilatation of intrahepatic and extrahepatic bile ducts, neck of pancreatic duct was narrowed and the remaining areas were thickened. Results of CT examination showed multiple stones in the neck of the gallbladder and in the common bile duct, accompanied by dilatation of the intrahepatic and extrahepatic bile ducts and the main pancreatic duct, and the lower end of the common bile duct was slightly narrow which mean the possibility of ampulla space occupying could not be excluded. Results of preoperative endoscopic ultrasonography examination showed soft tissue occupation at the lower end of the common bile duct which considering as the possibility of entophytic adenoma, and small stones in the common bile duct. Results of preoperative endoscopic ultrasonography biopsy showed chronic inflammation of duodenal papilla. Results of intraoperative rapid frozen histopathological examination showed chronic inflammation of duodenal papilla. Results of intraoperative choledochoscopy examination and electronic staining under choledochoscope showed smooth mucosa of duodenal papilla, without lesion. Results of intraoperative choledochoscopy examination with endobronchial ultrasonography showed clear structure of mucosa and submucosal of duodenal papilla, without lesion.Conclusion:Choledochoscopy can be used in the auxiliary diagnosis of cholelithiasis related diseases.

Objective To develop double-arc volumetric modulated arc therapy ( VMAT) plans using standard phantom and standard target volume in AAPM119 report, and to investigate the dosimetric parameters of Agility and MLCi2 leafs according to the requirements for target dose in AAPM119 report. Methods The Cshape, Head and Neck, Prostate, and Multitarget structures for standard target volume delineation in AAPM119 report were used.The Elekta Agility multi-leaf collimator was used to develop plans, and then with other parameters remaining unchanged, Elekta MLCi2 was used for plan optimization and dose calculation.The target dose in AAPM119 report was used as the standard to analyze the differences in target volume and dose-volume parameters of organs at risk between the four structures for target volume delineation.Results According to the mean dose in AAPM119 report, in the Cshape, Head and Neck, and Multitarget target volumes, the radiotherapy plans developed with Agility had better dosimetric parameters compared with those developed with MLCi2.In the prostate target volume, the radiotherapy plans developed with MLCi 2 had better dosimetric parameters compared with those developed with Agility .Conclusions With the structures for target volume delineation, plan designing personnel, designing parameters, and evaluation criteria remaining the same, Elekta Agility can achieve the dose target better than Elekta MLCi2 in the aspect of strict dose limit.

Objective To analyze the clinical value of postoperative radiotherapy for node-positive middle thoracic esophageal squamous cell carcinoma ( TESCC ) and to modify the target volume .Methods A total of 286 patients with node-positive middle TESCC underwent radical surgery in Cancer Hospital, Chinese Academy of Medical Sciences, from 2004 to 2009.In addition, 90 of these patients received postoperative intensity-modulated radiotherapy.The Kaplan-Meier method was used to calculate survival rates, and the log-rank test was used for survival difference analysis.The Cox model was used for multivariate prognostic analysis.The chi-square test was used for comparing the recurrence between patients receiving different treatment modalities.Results The 5-year overall survival ( OS) rates of the surgery alone ( S) group and surgery plus postoperative radiotherapy ( S+R) group were 22.9%and 37.8%, respectively, and the median OS times were 23.2 and 34.7 months, respectively ( P=0.003) .For patients with 1 or 2 lymph
node metastases (LNMs), the 5-year OS rates of the S group and S+R group were 27.3%and 44.8%, respectively ( P=0.017);for patients with more than 2 LNMs, the 5-year OS rates of the S group and S+R group were 16.7%and 25.0%, respectively (P=0.043).The peritoneal lymph node metastasis rates of N1 , N2 , and N3 patients in the S group were 2.9%, 10.9%, and 20.0%, respectively ( P=0.024) .The S+R group had a significantly lower mediastinal lymph node metastasis rate than the S group ( for patients with 1 or 2 LMNs:8.0%vs.35.3%, P=0.003;for patients with more than 2 LNMs, 10.0%vs.42.3%, P=0.001) , and had a prolonged recurrence time compared with the S group ( 25.1 vs.10.7 months, P=0.000) .However, for patients with more than 2 LNMs, the S+R group had a significantly higher hematogenous metastasis rate than the S group (46.7%vs.26.1%, P=0.039).Conclusions Patients with node-positive middle TESCC could benefit from postoperative radiotherapy.The target volume can be reduced for patients with 1 or 2 LNMs.Prospective studies are needed to examine whether it is more appropriate to reduce the radiotherapy dose than to reduce the target volume for patients with more than 2 LNMs.A high hematogenous metastasis rate warrants chemotherapy as an additional regimen.

[ Abstract] Objective To investigate the clinical efficacy of preoperative three-dimensional radiotherapy (3DRT) with or without concurrent chemotherapy for esophageal carcinoma.Methods We retrospectively analyzed 103 esophageal carcinoma patients who received preoperative 3DRT with or without concurrent chemotherapy from 2004 to 2014 in Cancer Hospital CAMS.The median radiation dose was 40 Gy, and the TP or PF regimen was adopted for concurrent chemotherapy if needed.The overall survival (OS) and disease-free survival ( DFS) were calculated by the Kaplan-Meier method, and the survival difference and univariate prognostic analyses were performed by the log-rank test.The Cox proportional hazards model was used for multivariate prognostic analysis.Results The number of patients followed at 3-years was 54.The 3-year OS and DFS rates were 61.1% and 54.9%, respectively, for all patients.There were no significant differences between the 3DRT and concurrent chemoradiotherapy (CCRT) groups as to OS (P=0.876) and DFS (P=0.521).The rates of complete, partial, and minimal pathologic responses of the primary tumor were 48.0%, 40.2%, and 11.8%, respectively.There were significant differences in OS and DFS between the complete, partial, and minimal pathologic response groups (P=0.037 and 0.003). No significant difference in pathologic response rate was found between the 3DRT and CCRT groups (P=0.953).The lymph node metastasis rate was 26.5%, and this rate for the complete, partial, and minimal pathologic response groups was 14%, 30%, and 67%, respectively, with a significant difference between the three groups (P=0.001).The OS and DFS were significantly higher in patients without lymph node metastasis than in those with lymph node metastasis (P=0.034 and 0.020).The surgery-related mortality was 7.8% in all patients.Compared with the 3DRT group, the CCRT group had significantly higher incidence rates of leukopenia (P=0.002), neutropenia (P=0.023), radiation esophagitis (P=0.008), and radiation esophagitis ( P=0.023).Pathologic response of the primary tumor and weight loss before treatment were independent prognostic factors for OS and DFS (P=0.030,0.024 and P=0.003,0.042). Conclusions Preoperative 3DRT alone or with concurrent chemotherapy can result in a relatively high complete pathologic response rate, hence increasing the survival rate.Further randomized clinical trials are needed to confirm whether preoperative CCRT is better than 3DRT in improving survival without increasing the incidence of adverse reactions.

Objective To study the impact of respiratory frequency and amplitude of patients with the thoracic or abdomen tumor on 4DCT' s reconstructed image.Methods 75 thoracic or abdomen tumor patients who performed a scanning with belly belt-type respiratory gating on 4DCT between November 2012 to March 2013 in our hospital were retrieved.Reviewed their respiratory frequency,amplitude and fault distance of 4DCT' s reconstructed image and analyzed the correlation fault distance of the reconstructed image.The correlation analysis was used by bivariate Spearman method.Results Among these reconstructed images,fault distance more than 6 mm could be seen in 11 cases,fault distance ranging from 3 mm to 6 mm could be found in 46 cases,and distance less than 3 mm could be detected in 18 case.Respiratory frequency correlated significantly with the amplitude (rs =0.369,P =0.000);the respiratory rate had a tight association with the fault distance of the reconstructed image (r,=0.273,P=0.018);and respiratory amplitude was associated obviously with the fault distance of the reconstructed image (r,=0.696,P=0.000).Conclusions Both 4DCT reconstructed image and respiratory amplitude are significantly correlated to the continuity of the respiratory frequency.The smaller the respiratory frequence and amplitude change are,the better continuity will be.

OBJECTIVEVideo-assisted thoracoscopic (VATS) esophagectomy has been performed for more than 10 years in China. However, compared with the conventional esophagectomy via right thoracotomy, whether VATS esophagectomy has more advantages or not in the lymph node (LN) dissection and prevention of perioperative complications is still controversial and deserves to be further investigated. The aim of this study was to explore whether there are significant differences in this issue between the two surgical modalities or not.

METHODSThe results of lymph node dissection and perioperative complications as well as other parameters in the patients treated by VATS esophagectomy and those by conventional esophagectomy via right thoracotomy at our department from May 1, 2009 to July 30, 2013 were compared using SPSS 16.0 in order to investigate whether there was any significant difference between these two treatment modalities in the learning curve stage of VATS esophagectomy.

RESULTSOne hundred and twenty-nine cases underwent VATS esophagectomy between May 1, 2009 and July 30, 2013, and another part 129 cases with the same preoperative cTNM stage treated by conventional esopahgectomy via right thoracotomy were selected in order to compare the results of lymph node dissection and perioperative complications as well as other parameters between those two groups of patients. There were no significant differences in the sex, age, lesion locations and cTNM stage between these two groups. The total LN metastatic rate in the VATS esophagectomy group was 35.7% and that of the conventional esophagectomy group was 37.2% (P > 0.05). The total average number of dissected lymph nodes was 12.1 vs. 16.2 (P < 0.001). The average dissected LN stations was 3.2 vs. 3.6 (P = 0.038). The total average number of dissected LN along the left recurrent laryngeal nerve was 2.0 vs. 3.7 (P = 0.012). The total average number of dissected LN along the right recurrent laryngeal nerve was 2.9 vs. 3.4 (P = 0.231). However, there was no significant difference in the total average number of dissected LN in the other thoracic LN stations, and in the perioperative complications between the two groups. The total postoperative complication rate was 41.1% in the VATS group versus 42.6% in the conventional group (P = 0.801). The cardiopulmonary complication rate was 25.6% vs. 27.1% (P = 0.777). The death rate was the same in the two groups (0.8%). The VATS group had less blood infusion (23.2% vs. 41.8%, P = 0.001) and shorter hospital stay (15.9 days vs. 19.2 days, P = 0.049) but longer operating time (161.3 min vs. 127.8 min, P < 0.01).

CONCLUSIONSIn the learning curve stage of VATS esophagectomy, compared with the conventional esophagectomy, less LN number and stations can be dissected in the VATS group due to un-skillful VATS manipulation, especially it is more difficult in the LN dissection along the left recurrent laryngeal nerve. Therefore, it is more suitable to select patients with early esophageal cancer without obvious enlarged lymph nodes for VATS esophagectomy in the learning curve stage.

China ; Esophageal Neoplasms ; pathology ; surgery ; Esophagectomy ; adverse effects ; methods ; Humans ; Learning Curve ; Length of Stay ; Lymph Node Excision ; adverse effects ; methods ; statistics & numerical data ; Lymph Nodes ; Operative Time ; Postoperative Complications ; epidemiology ; Recurrent Laryngeal Nerve ; Thoracic Surgery, Video-Assisted ; adverse effects ; Thoracotomy

Objective Video?assisted thoracoscopic ( VATS ) esophagectomy has been performed for more than 10 years in China. However, compared with the conventional esophagectomy via right thoracotomy, whether VATS esophagectomy has more advantages or not in the lymph node ( LN) dissection and prevention of perioperative complications is still controversial and deserves to be further investigated. The aim of this study was to explore whether there are significant differences in this issue between the two surgical modalities or not. Methods The results of lymph node dissection and perioperative complications as well as other parameters in the patients treated by VATS esophagectomy and those by conventional esophagectomy via right thoracotomy at our department from May 1,2009 to July 30,2013 were compared using SPSS 16.0 in order to investigate whether there was any significant difference between these two treatment modalities in the learning curve stage of VATS esophagectomy. Results One hundred and twenty?nine cases underwent VATS esophagectomy between May 1, 2009 and July 30, 2013, and another pared 129 cases with the same preoperative cTNM stage treated by conventional esopahgectomy via right thoracotomy were selected in order to compare the results of lymph node dissection and perioperative complications as well as other parameters between those two groups of patients. There were no significant differences in the sex, age, lesion locations and cTNM stage between these two groups. The total LN metastatic rate in the VATS esophagectomy group was 35.7% and that of the conventional esophagectomy group was 37.2% (P>0.05). The total average number of dissected lymph nodes was 12.1 vs. 16.2 ( P<0.001) . The average dissected LN stations was 3.2 vs. 3.6 ( P=0.038) . The total average number of dissected LN along the left recurrent laryngeal nerve was 2.0 vs. 3.7 ( P=0.012) . The total average number of dissected LN along the right recurrent laryngeal nerve was 2.9 vs. 3.4 (P=0.231). However, there was no significant difference in the total average number of dissected LN in the other thoracic LN stations, and in the perioperative complications between the two groups. The total postoperative complication rate was 41. 1% in the VATS group versus 42. 6% in the conventional group ( P=0.801) . The cardiopulmonary complication rate was 25.6% vs. 27.1% ( P=0.777) . The death rate was the same in the two groups (0.8%). The VATS group had less blood infusion (23.2% vs. 41.8%, P=0.001) and shorter hospital stay (15.9 days vs. 19.2 days, P=0.049) but longer operating time (161.3 min vs. 127.8 min, P<0.01). Conclusions In the learning curve stage of VATS esophagectomy, compared with the conventional esophagectomy, less LN number and stations can be dissected in the VATS group due to unskillful VATS manipulation, especially it is more difficult in the LN dissection along the left recurrent laryngeal nerve. Therefore, it is more suitable to select patients with early esophageal cancer without obvious enlarged lymph nodes for VATS esophagectomy in the learning curve stage.