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 observe the clinical efficacy of Tongfengke Granules combined with external treatment of TCM in acute gouty arthritis(AGA)with damp-heat accumulation type.Methods A total of 96 patients with AGA were divided into the experimental group and the control group according to random number table method,with 48 patients in each group.The control group received meloxicam treatment.On this basis,the experimental group was treated with Tongfengke Granules(1 bag at a time,three times a day,orally)combined with external therapy of TCM(once a day),and mobile continuing care.The treatment for both groups lasted for 2 weeks.The clinical efficacy of both groups was observed.Before and after the treatment,pain visual analogue scale(VAS),TCM syndrome scores,major symptom scores,and levels of serum uric acid(UA),interleukin-6(IL-6),erythrocyte sedimentation rate(ESR),C-reactive protein(CRP),platelet/lymphocyte ratio(PLR),as well as engagement in self-care ability scale(ESCA),general self-efficacy scale(GSES),negative psychological condition[self-rating depression scale(SDS),self-rating anxiety scale(SAS)]were measured.The adverse reactions in both groups were monitored.Results Totally 45 and 47 patients in the experimental group and control group were finally included respectively in the analysis.The total effective rate of the experimental group was 75.6%(34/45),while that of the control group was 63.8%(30/47),with statistical significance(P<0.05).Compared with before treatment,the VAS score and TCM syndrome score in the experimental group decreased significantly(P<0.05);after treatment,the VAS score and TCM syndrome score of the experimental group were lower than those of the control group(P<0.05).Compared with before treatment,the joint pain,joint tenderness,joint swelling,and joint mobility limitation scores in both groups were significantly decreased after treatment(P<0.05,P<0.01);after treatment,the scores of joint pain,joint tenderness,and joint swelling in the experimental group were lower than those in the control group(P<0.01).Compared with before treatment,the levels of UA,ESR,CRP and PLR in both groups decreased significantly after treatment(P<0.01);after treatment,the levels of UA,ESR,CRP and PLR in the experimental group were lower than those in the control group(P<0.05,P<0.01).Compared with before treatment,the experimental group showed significant improvement in ESCA,GSES and SAS after treatment(P<0.05,P<0.01),while the control group showed significant improvement in ESCA(P<0.01);after treatment,the ESCA and GSES of the experimental group were better than those of the control group(P<0.05,P<0.01).There was no statistical significance in safety indicators and incidence of adverse reactions between the two groups(P>0.05).Conclusion Tongfengke Granules combined with external treatment of TCM can significantly improve the clinical efficacy of AGA,reduces UA levels,significantly improves inflammatory response,and has anti-inflammatory,anti-inflammatory,and analgesic effects.

Objective:To compare the histopathological features and treatment efficacy of different methods for metachronous early gastric cancer (MEGC) in the remnant stomach.Methods:A total of 66 patients [38 endoscopic submucosal dissection (ESD) and 28 gastrectomy] with MEGC in the remnant stomach from January 2014 to December 2020 in Drum Tower Hospital were divided into the ESD group and the gastrectomy group. The baseline characteristics, histopathological features, treatment efficacy, and cost differences of the two groups were analyzed.Results:The MEGC in the remnant stomach mostly occurred in elderly male patients, with the mean age of 69.7±8.5 years. The mean interval of the occurrence of MEGC in the remnant stomach was 6 years. As for the tumor location, the gastric body (31.6%) was the main location in the ESD group and gastric cardia (53.6%) in the gastrectomy group with significant difference ( χ2=11.07, P=0.026). The mean operation time, hospital stay, postoperative fasting time, and total treatment cost were 80.0 min, 6.0 d, 1.5 d, ￥19 436 in the ESD group and 215.0 min, 19.0 d, 6.5 d, and ￥68 665 in the gastrectomy group, respectively, with significant differences between the two groups ( P<0.05). The overall survival rate during follow-up was 76.3% in the ESD group and 71.4% in the gastrectomy group with no significant difference between the two groups ( χ2=0.736, P=0.778). In terms of postoperative complications, the incidences of bleeding and infection were 7.9% and 5.3% in the ESD group, and those of obstruction and infection were both 14.3% in the gastrectomy group. There was significant difference in the incidences of postoperative obstruction between the two groups ( P<0.05). Conclusion:ESD is safe and effective for MEGC in the remnant stomach and is better than gastrectomy in terms of the treatment cost and operation time, but the long-term efficacy still needs to be validated by large-scale prospective studies.

Objective:To compare the safety and efficacy of laparoscopy and laparotomy for 5-10 cm intermediate-risk gastric stromal tumor, and to evaluate whether there was evident benefits of postoperative adjuvant treatment with imatinib.Methods:A retrospective study was conducted on 72 patients with moderate risk gastric stromal tumors (5-10 cm in diameter) who received operation in Nanjing Drum Tower Hospital from January 2010 to July 2020. There were 28 cases in the laparoscopy group and 44 cases in the laparotomy group. The clinical features, pathological data, perioperative results and hospitalization costs were compared between the two groups. The survival rates of postoperative adjuvant therapy with or without imatinib were analyzed and compared.Results:There was no significant difference in clinicopathological features between the two groups ( P>0.05). The incidences of postoperative complications in the laparoscopy group and the laparotomy group were 32.1% (9/28) and 52.3% (23/44) respectively, showing no significant difference ( P=0.094). Compared with the laparotomy group, both the hospital stay (12.5±3.2 days VS 15.0±3.5 days, P=0.004) and the median postoperative hospital stay (7.5 days VS 9.0 days, P=0.006) in the laparoscopy group were significantly shorter, and the first exhaust time was significantly shorter ( P=0.003). During the median follow-up period of 58 months (13-129 months), there was no tumor-related death. Two cases died of breast cancer and heart disease in the laparotomy group, and 1 case died irrelevant to gastric stromal tumor in the laparoscopy group. Of the 72 patients, 40 received postoperative imatinib adjuvant therapy, 22 cases (50.0%) in the laparotomy group and 18 cases (64.3%) in the laparoscopy group, with no significant difference in the proportion ( χ2=1.414, P=0.234). There was significant difference in the overall survival rate between the group treated with imatinib and the group without imatinib ( P=0.015). Conclusion:Laparoscopic resection is safe and effective for intermediate-risk gastric stromal tumor of 5-10 cm. Taking imatinib adjuvant treatment does not increase overall survival rate of patients with intermediate-risk gastric stromal tumors (5-10 cm), and there is no tumor-related death, recurrence or metastasis for those who did not accept imatinib adjuvant treatment after R0 resection.

Objective:To evaluate the long-term efficacy of endoscopic transluminal drainage(ETD) for acute pancreatitis complicated with walled-off necrosis (WON) or pancreatic pseudocyst (PPC).Methods:A total of 79 patients who were diagnosed as having WON or PPC by abdominal CT or ultrasound and treated with ETD in Nanjing Drum Tower Hospital were enrolled. Past medical records and follow-up by phone call after discharge were analyzed for long-term outcomes including endocrine and exocrine functions and long-term quality of life.Results:A total of 50 patients were enrolled, including 31 patients with infected WON/PPC and 19 patients with uninfected WON/PPC. Seventeen patients (54.84%) in the infected WON/PPC group and 11 patients (57.89%) in the uninfected WON/PPC group lost 5% or more of their weight. There were no significant differences in the proportion of cases of weight loss of 5% or more ( P=0.833), or the weight loss between the two groups (12.59±8.89 kg VS 10.91±2.47 kg, P=0.522). Only one patient in the infected WON/PPC group had chronic abdominal pain. There was no significant difference in the Izbicki score between the two groups (23.79±6.74 VS 22.03±3.21, P=0.295). None of the patients developed steatorrhea after discharge. Five patients (16.67%, 5/30) in the infected WON/PPC group and 6 patients (40.00%, 6/15) in the uninfected WON/PPC group developed endocrine insufficiency with no significant difference ( P=0.140). Greater risk of secondary diabetes resulted from higher low-density lipoprotein cholesterol ( HR=1.9, 95% CI: 1.0-3.4, P=0.044)and triglycerides ( HR=1.2, 95% CI: 1.0-1.3, P =0.029). Conclusion:ETD is safe and effective for WON and PPC. But there is possibility that patients develop secondary diabetes. Additionally, greater risk of secondary diabetes results from higher low-density lipoprotein cholesterol and triglycerides.

OBJECTIVE: To explore the effect of job burnout of medical staffs on their mental health and the regulating effect of social support and mediating effect of coping style. METHODS: A total of 758 medical staffs in a city of Shandong Province were selected as study subjects by stratified random sampling method and investigated using the Maslach Burnout Questionnaire,General Health Questionnaire,Social Support Rating Scale and Trait Coping Style Questionnaire. RESULTS: Job burnout was negatively associated with social support and positive coping( P < 0. 01),and positively associated with mental health and negative coping( P < 0. 01). Both social support and positive coping style showed a negative correlation with mental health( P < 0. 01). A positive correlation was found between negative coping styles and mental health( P <0. 01). Job burnout showed a direct positive prediction function to mental health [standardized regression coefficients( β) = 0. 28,P < 0. 01]. The subjective support dimensions of social support played a role of negative prediction in regulating job burnout and mental health( β =-0. 10,P < 0. 01). Coping styles played a mediating role in job burnout and mental health. Job burnout affected mental health problems by reducing the positive coping and increasing the partial intermediary role of negative coping,the mediation effect was 10. 9%. CONCLUSION: The medical staffs in Shandong Province have low incidence of job burnout. Job burnout shows negative effect on mental health. Subjective support feelings from social support and positive coping style are important protective factors.

Objective To explore the mechanism of notch signaling pathway in the treatment of cervical cancer with notch receptor blocker(DAPT).Methods After treatment of Me180 cells with different concentrations of DAPT combined with curcumin-photodynamic therapy (PDT),3-(4,5 Dimethylthiazlo-yl)-2,5 Dimethylthiazol-2-yl)-2,5 dipheny tetrazo lium bromide(MTT)assay was used to detect the effect on the proliferation of Me180 cells,annexin V-FITC/PI combined with flow cytometry was used to detect the effect on apoptosis,and real-time fluorescence quantitative PCR and Western blot were used to detect the mRNA and protein expressions of Notch1 gene respectively.Results Both DAPT(1.0 μmol/L)and curcumin-PDT groups could inhibit the proliferation and induce apoptosis of cervical cancer cell line Me180,and the synergistic effect of the two groups was significant (P＜0.05 or＜0.01).DAPT and curcumin-PDT group reduced the mRNA expression level of Notch1 in cervical cancer Me180 cells with inhibition ratio of 40.0％ and 32.3％ respectively.DAPT and curcumin-PDT group inhibited the protein expressions of Notch1,nuclear factor-kappa B(NF-kB),vascular endothelial growth factor (VEGF),and the synergistic effect of the two groups was statistically significant.Conclusions Both DAPT and curcumin-PDT may effectively block the conduction of Notch signaling pathway,which is associated with down-regulation of the expression of Notch1 and NF-kappa B.Notch signaling pathway may be one of the targets of curcumin photodynamic therapy.

Objective To explore the correlation between self-concept and subjective quality of life among children with tic disorders (TD). Methods The Piers-Harris Children's Self-concept Scale (PHCSS) and the Inventory of Subjective Life Quality (ISLQ) were complet-ed by 65 children with TD and 71 normal children from March to September, 2015; and analyzed with single factor analysis, correlation analysis and multi factors regression analysis. Results There was no significant difference in PHCSS scores between the TD children with and normal ones (t<1.624, P>0.05). The ISLQ scores of school life, self-awareness and cognitive component were less in the TD children than in the normal ones (t>2.051, P<0.05). The PHCSS subscores correlated with ISLQ subscores (P<0.05), except the following:PHCSS scores of behavior did not correlate with ISLQ scores of peer relationship, school life, living environment, self-awareness and cognitive com-ponent;PHCSS scores of intelligence and school environment did not correlate with ISLQ scores of family life, peer interaction and the liv-ing environment;PHCSS scores of physical appearance and properties did not correlate with ISLQ scores of family life and living environ-ment;PHCSS scores of anxiety did not correlate with ISLQ scores of family life, peer interaction and cognitive component;PHCSS scores of affiliation did not correlate with ISLQ scores of peer interaction;and PHCSS total score did not correlate with ISLQ scores of family life and living environment. PHCSS scores of affiliation were the factor related with the quality of life (β=0.301, P<0.05). Conclusion The quali-ty of life may be impaired in the children with TD, which may associate with the self-concept and need further intervention.

Objective To investigate the correlation between serum homocysteine (HCY) and chronic heart failure (CHF) hypercoagulable state in patients.Methods A total of 105 cases of patients with CHF was divided into three groups according to the New York Heart Association (NYHA) classification standard functions:heart functional grade Ⅱ group (42cases),cardiac function grade Ⅲ group (35 cases) and,NYHA class Ⅳ group (28cases).At the same time,40 healthy individuals were regard as the control group.HCY,fibrinogen (Fbg),D-dimer (DDI),HCY,N-terminal pro-brain natriuretic peptide (NT-proBNP) were detected by fasting venous blood samples which were collected within 24 hours after admission.Results Compared to the control group,the expression of Fbg,DDI,HCY and NT-proBNP increased,whereas,antithrombin Ⅲ (AT-Ⅲ) was reduced.Fbg,DDI,HCY,NT-proBNP,and AT-Ⅲ were found in all patient cases.Four groups were compared with each other,except for cardiac function Ⅱ group and the normal group had no significant difference between them (P ＞ 0.05),the difference between both other groups was significantly different (P ＜ 0.05),HCY had a positive correlation with Fbg,DDI,and NT-proBNP (r =0.268,0.295,and 0.404,P ＜ 0.05),and negative correlation with AT-Ⅲ (r =-0.240,P ＜ 0.05).Conclusions HCY might be a reliable indicator as a judge of CHF patients with hypercoagulable state,to detect HCY,FBG,DDI,and AT-Ⅲ in CHF patients.It benefits for judging thrombosis risk and determining the severity of the diseases.Anticoagulant therapy might be beneficial to reduce the long-term adverse events.

Objective To explore the influence of obstruction sleep apnea syndrome (OSAS) on plasma cystatin C (CC) levels in patients with primary hypertension.Methods A total of 244 cases of primary hypertension patients was chosen.The patients were divided into observation group (with OSAS) and control group (without OSAS) according to apnea hypopnea index (AHI).The observation group was then divided into three subgroups:mild OSAS group,moderate OSAS group,and severe OSAS group.The levels of CC were compared.Results First,the plasma CC levels in patients with primary hypertension had no statistical significance in the differences among different grades of hypertension (P ＞ 0.05).Second,CC levels of observation group were significantly higher than control group (P ＜ 0.05).Third,CC levels of the severe group were higher than the moderate group,and the plasma CC levels of the moderate group were also higher than the mild group and control group.Rank correlation analysis and comparison of CC levels and AHI showed that CC levels were positively correlated with AHI (r =0.585,P ＜ 0.01).However,there were no statistically significant differences between CC levels of the mild OSAS group and control group (P ＞ 0.05).Conclusions The patients with OSAS and primary hypertension had higher levels of CC,and aggravated with the progress of the degree of obstruction.CC may be involved in the progression of the disease,a high level of CC may aggravate the condition,it should be early prevention and treatment.