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.

The minimal persistent inflammation(MPI)of allergic rhinitis(AR)is asymptomatic inflammation that occurs locally in the nasal mucosa after exposure to low doses of allergens.With the study of MPI,researchers have realized that this local sub-clinical inflammation in patients with AR not only causes chronic damage to the nasal mucosa,but also increases the hypersensitivity and hyperresponsiveness of allergic airway disease.The concept of MPI has changed our strategy for the treatment of AR,which re-quires that we should not only intervene in the symptomatic exacerbation period,but also intervene in the asymptomatic MPI period.This article systematically reviews the immunological mechanism,adverse effects,and treatment strategies of the MPI,to provide bet-ter treatment for the MPI of AR and reduce the recurrence of AR.

Objective:To investigate the clinicopathological features, diagnosis and differential diagnosis of adrenal cortical carcinoma (ACC) in children.Methods:Twenty-five children with ACC diagnosed in the Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from March 2014 to August 2022 were retrospectively analyzed. The related literature was reviewed.Results:A total of 25 children with ACC were collected, including 11 males and 14 females, with a male to female ratio of 1.0∶1.3. The patient ages ranged from 8 months to 14 years (median, 4 years). Eighteen cases with clinical data had functional tumors (18/22, 81.8%) presenting with virilization or precocious puberty (15/18), symptoms related to hypercortisolism (8/18) or endocrine symptoms mixed with both (5/18), while 3 cases (3/22, 13.6%) had unknown clinical data. The clinical manifestations of four patients with nonfunctional tumors were an abdominal mass and/or abdominal pain, walking instability and others. Grossly, the average maximum diameter of the tumor was 9.4 cm. Most of the tumors were nodular and partially encapsuled. The cut surfaces were gray or gray brown, soft with hemorrhage. Histologically, the tumor cells were diffusely distributed, separated by a vascular-rich network. The tumor cells were large, with distinct nucleoli, abundant eosinophilic or clear cytoplasm, and round or oval nuclei. The mitotic index was high, and atypical mitoses were common. Necrosis, calcification, capsule invasion or/and venous invasion were present. In some cases, the tumor invaded the surrounding soft tissues or kidneys. Immunohistochemically, the tumor cells were diffusely positive for syn and SF1 and focally positive for α-inhibin, Melan A and Calretinin, but negative for CgA. Ki-67 proliferation index ranged from 2%-90%. TP53 gene status was examined in 7 cases, in which mutations were detected in 4 cases. Follow-up data was obtained in 21 patients, among whom 18 received chemotherapy and 3 received radiotherapy. Distant metastasis occurred in 13 patients. Median progression-free survival (PFS) was 11.2 months and median overall survival (OS) was 54.7 months. Patients aged less than 5 years had a better prognosis for OS ( P<0.05) than the older ones (≥5 years), but a similar PFS ( P>0.05). Male patients and Ki-67 proliferation index <15% had a better prognosis tendency for OS, but there was no statistically significant difference ( P>0.05). Conclusions:ACC in children is a rare, often functional tumor associated with Li-Fraumeni genetic syndrome and has a poor prognosis. Diagnosis and differential diagnosis require a combination of morphological, phenotypic and clinical analysis.

Objective:To observe the efficacy and safety of the M receptor antagonist Bencycloquidium bromide nasal spray in treatment of seasonal allergic rhinitis with runny nose as the main symptom. Methods:From August 2021 to September 2021, 134 patients with seasonal allergic rhinitis were enrolled in the otolaryngology Outpatient Department of Peking University Third Hospital, First Affiliated Hospital of Harbin Medical University and China-Japanese Friendship Hospital of Jilin University, including 71 males and 63 females, with a median age of 38 years. TNSS score and visual analogue scale（VAS） of total nasal symptoms were observed during 2 weeks of treatment with Bencycloquidium bromide nasal spray. Results:TNSS score decreased from （8.89±3.31） on day 0 to （3.71±2.51） on day 14（P<0.001）, VAS score of nasal symptoms decreased from （24.86±7.40） on day 0 to （6.84±5.94） on day 14（P<0.001）, VAS score of rhinorrhoea decreased from （6.88±2.06） on day 0 to （1.91±1.81） on day 14（P<0.001）. Rhinoconjunctivitis quality of life questionnaire（RQLQ） score decreased from （94.63±33.35） on day 0 to （44.95±32.28） on day 14（P<0.001）. The incidence of adverse reaction was low and no serious adverse events occurred during the whole experiment. Conclusion:Bencycloquidium bromide nasal spray has significant efficacy and good safety in the treatment of seasonal allergic rhinitis.
Male ; Female ; Humans ; Adult ; Rhinitis, Allergic, Seasonal/drug therapy* ; Nasal Sprays ; Quality of Life ; Administration, Intranasal ; Rhinorrhea ; Double-Blind Method ; Treatment Outcome ; Rhinitis, Allergic/drug therapy*

Background Stroke has become a main cause of death in China. With global warming, the studies on temperature and stroke have attracted much attention. Objective To analyze he relationships between heatwave and the years of life lost (YLL) by different subtypes of stroke by controlling temporal and spatial effects with Bayesian spatio-temporal model, and to study the modifiers of the health effect of heatwave. Methods The daily information of stroke deaths, meteorological data, and air pollutant data in 40 districts and counties of Guangdong Province were collected during the warm seasons (from May to October) in the years from 2014 to 2017. The individual YLL was first calculated by matching age and gender according to the life table, and then the daily YLL rate (person-years/100 000 people) was obtained by summarizing the daily YLL and correcting it with the population of each district or county. Bayesian spatio-temporal model was used to fit a proposed exposure-response relationship between heatwave and the YLL rates of different subtypes of stroke. Finally, stratified analyses were conducted by age (<65 years, ≥65 years), gender (male, female), and region (Pearl River Delta and non-Pearl River Delta regions) to identify the major modifiers for the association between heatwave and stroke mortality. Results During the warm seasons from 2014 to 2017, a total of 23 heatwave events occurred in the 40 districts or counties of Guangdong Province, cumulatively lasting for 145 d. A total of 30 852 stroke deaths were recorded in the same time periods. The average daily YLL rate of total stroke was (2.39±3.63) person-years/100 000 people, and those for hemorrhagic stroke and ischemic stroke were (1.54±2.99) person-years/100 000 people and (0.84±1.85) person-years/100 000 people, respectively. Heatwave was associated with increased YLL rate of stroke in residents, and it had a greater impact on ischemic stroke with a lag effect. The largest cumulative effect of heatwave was at lag 0-1 day, which was associated with an increased YLL rate of total stroke and ischemic stroke by 0.17 (95%CI: 0.03-0.29) person-years/100 000 people and 0.13 (95%CI: 0.06-0.20) person-years/100 000 people, respectively. The results of stratified analyses showed that heatwave had a larger effect on ischemic stroke in residents of aged 65 years or older, male, and non-Pearl River Delta regions, and the rates of YLL increased by 1.11 (95%CI: 0.58-1.55), 0.13 (95%CI: 0.03-0.23), and 0.20 (95%CI: 0.07-0.32) person-years/100 000 people, respectively; Heatwave only had an effect on hemorrhagic stroke in residents aged 65 years or older with an increased YLL rate of 0.79 (95%CI: 0.26-1.31) person-years/100 000 people. Conclusion Heatwave could elevate the level of years of life lost associated with stroke in Guangdong residents, with greater impacts on ischemic stroke of the aged, men, and residents in non-Pearl River Delta regions, and on hemorrhagic stroke in the elderly.

Objective:To investigate the prevalence of Escherchia albertii in Shanxi province. Methods:The chicken intestines were enriched in EC broth. The eae gene was detected by PCR, and the eae-positive EC enrichments were inoculated in MacConkey agar plate. The eae-positive lactose non-fermenting isolates were presumed as Escherchia albertii, and then analyzed by triplex-PCR, 16S rDNA sequencing and MLST. Results:Two suspected Escherchia albertiiwere isolated from 250 samples of chicken intestines. It was identified as Escherchia albertii by phenotypic, specific genes,16S rDNA sequencing, and MLST analyses . The cytolethal distending toxin B ( cdtB) showed positive by PCR,and they were clusted to Ⅱ/Ⅲ/Ⅴ group by sequencing. Conclusion:This study showed that the Escherchia albertii was existed in Shanxi province, China.

Objective:To investigate the prevalence of Escherchia albertii in Shanxi province. Methods:The chicken intestines were enriched in EC broth. The eae gene was detected by PCR, and the eae-positive EC enrichments were inoculated in MacConkey agar plate. The eae-positive lactose non-fermenting isolates were presumed as Escherchia albertii, and then analyzed by triplex-PCR, 16S rDNA sequencing and MLST. Results:Two suspected Escherchia albertiiwere isolated from 250 samples of chicken intestines. It was identified as Escherchia albertii by phenotypic, specific genes,16S rDNA sequencing, and MLST analyses . The cytolethal distending toxin B ( cdtB) showed positive by PCR,and they were clusted to Ⅱ/Ⅲ/Ⅴ group by sequencing. Conclusion:This study showed that the Escherchia albertii was existed in Shanxi province, China.

To compare the intra cuff pressure changes during improved and the traditional method of cuff pressure measurement, then evaluate the effects of ventilator-associated pneumonia (VAP) prevention. The results highlighted practical recommendations in the process of ETT cuff pressure measurement. Methods① Experimental studies were carried out on the tracheal model with two groups: traditional pressure measurement group and improved pressure measurement group. The traditional pressure measurement group was connected to a handheld pressure gauge with the indicate cuff to get the intra-cuff pressure. The improved method was to insert a 3-way stopcock between the handheld pressure gauge and the indicate cuff. The 3-way stopcock to stabilize handheld pressure gauge reading at 32 cmH2O (1 cmH2O = 0.098 kPa) before measure the intra-cuff pressure. The pressure loss caused by two pressure measurement methods and the leakage of liquid on the balloon after 10 minutes was compared.② Clinical researches: a historic cohort study, patients with mechanical ventilation (MV) admitted to intensive care unit (ICU) of Guangxi Medical University Cancer Hospital from June 2014 to May 2018 were enrolled. The control group (249 cases) was treated with traditional method during June 2014 to May 2016, and the observation group (314 cases) was treated with improved method during June 2016 to May 2018. Clusters of strategies and actions of VAP prevention were applied in both groups. Incidence of VAP, duration of MV, and the length of ICU stay were compared between the two groups. Results ① Experimental study: the pressure leakage of the traditional pressure measurement group was (10.18±0.47) cmH2O, and that of the improved pressure measurement group was (1.33±0.42) cmH2O, with statistically significant difference between the two groups (t = 32.535, P = 0.000). All fluid on the cuffs leak after 10 minutes of traditional ways of measurement, however, no visible fluid on the cuffs leaked with improved procedures. ② Clinical research: the incidence of VAP in the observation group was slightly lower than that in the control group, however there was no significant difference [5.10% (16/314) vs. 8.43% (21/249), P > 0.05]. The duration of MV and the length of ICU stay in the observation group were significantly shorter than those in the control group (days: 9.93±3.14 vs. 16.77±5.45, 11.63 ±2.28 vs. 19.12±5.10, both P < 0.01). Conclusion The improved procedures of intra-cuff pressure measurement is a practical method to avoid the pressure leakage and fluid leakage, and the clinical course of MV patients can be significantly improved by combining the clusters of nursing strategies and actions.

Objective To investigate the expression of programmed death ligand 1 (PD-L1) in lung adenocarcinoma tissues and its correlation with clinicopathological features of patients. Methods A total of 141 paraffin-embedded specimens of patients with newly diagnosed lung adenocarcinoma by pathology from January to August 2018 in the Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School were collected. The expression of PD-L1 in the tumor cells (TC) and tumor-infiltrating immune cells (IC) were detected by immunohistochemistry EnVision staining. Based on the percentage of expression, PD-L1 in TC and IC were divided into TC3 (≥50％), TC2 (≥5％ and <50％), TC1 (≥1％ and <5％), and TC0 (<1％); IC3 (≥10％), IC2 (≥5％ and <10％), IC1 (≥1％ and <5％), and IC0 (<1％). Results PD-L1 expression was positive in 90 cases, and the positive rate was 63.8％ (90/141) at a TC1 or IC1 threshold. When a TC3 or IC3 threshold was applied, PD-L1 expression was positive in 17 cases, and the positive rate was 12.1％ (17/141). In the TC1 or IC1 threshold group, PD-L1 expressions were different in patients with different sex, nerve invasion and pleural invasion, and the differences were statistically significant (all P < 0.05). While in the TC3 or IC3 threshold group, PD-L1 expressions were different in patients with different cell differentiation, clinical stage, lymphocyte infiltration, vascular invasion and nerve invasion, and the differences were statistically significant (all P < 0.05). In both TC1 or IC1 threshold group and TC3 or IC3 threshold group, PD-L1 expression was associated with nerve invasion (both P < 0.05). Conclusions PD-L1 expression is associated with nerve invasion. PD-L1 inhibitors expect to be used as a potential treatment strategy for recurrent and progressive lung adenocarcinoma patients with high level expression of PD-L1.

Objective To analyze the regulatory of miRNA (miR)-149-5p for the expression of Aurora-B in esophageal squamous cell carcinoma (ESCC). Methods The pathologic histology paraffin blocks of 61 patients with ESCC in Shanxi Provincial People's Hospital from January 2010 to December 2017 were collected. The immunohistochemical staining and tissue section in situ hybridization method were used to observe the expressions of Aurora-B and miR-149-5p in the tumor tissues and adjacent mucosas of the patients, and their relationship with clinicopathological parameters was analyzed. miRNA was predicted by using software TargetScan and miR walk. The relationship between Aurora-B and miR-149-5p were verified by using Western blot in ESCC TE-1 cells. Results The result of immunohistochemical staining showed that in 61 patients, 37 (61％) tumor tissues showed higher expression of Aurora-B compared with adjacent mucosas, the Aurora-B expression in 15 (26％) tumor tissues were in line with benign tissues, the Aurora-B expression in 9 (13％) tumor tissues were inferior to benign tissues. The expression of Aurora-B were not correlated with age (χ2=0.008, P=0.929), gender (χ2=0.088, P=0.767), grade of differentiation (χ2=2.632, P=0.268), but correlated with TNM staging (χ2=15.153, P<0.01) and lymph node metastasis (χ2=5.979, P=0.014). The miR-149-5p was predicted to combine with Aurora-B 3'untraslated region (UTR) by using TargetScan and miRwalk software. The result of in situ hybridization showed that the miR-149-5p showed low expression in 22 (36％) tumor tissues. The expression of miR-149-5p was correlated with Aurora-B expression (χ2 = 5.622,P= 0.018), and not correlated with age (χ2= 2.617, P= 0.106), gender (χ2= 1.529, P= 0.216), grade of differentiation (χ2 = 2.854, P= 0.240), TNM staging (χ2 = 0.870, P= 0.351) and lymph node metastasis (χ2= 0.128, P= 0.351). The Western blot results of TE-1 cells showed that the expression of Aurora-B in simultaneous over-expression of miR-149-5p and Aurora-B group was higher than that in over-expression of miR-149-5p group, and lower than that in over-expression of Aurora-B group. Conclusion The miR-149-5p can be involved in ESCC progression through regulating the expressions of Aurora-B.