Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Child ; Humans ; Granulomatous Disease, Chronic/complications* ; Pneumonia

Objective It explores the importance and effectiveness perception of 55 third-tier indicators in the cur-rent performance evaluation system.Methods From the perspective of those being assessed,it employs survey ques-tionnaires,Importance Performance Analysis(IPA),and focus group interviews to conduct research on the impor-tance and effectiveness perception.Results The overall perception of the importance and effectiveness of third-tier in-dicators is relatively high,and the performance evaluation indicator system can effectively assess the development level of level-3 public hospitals.There is a general discrepancy between the perception of importance and effective-ness.Some third-tier indicators face issues of insufficient perception of both importance and effectiveness.Conclu-sion Performance evaluation policy formulation based on the implementation of policies and after excluding the scores of indicators closely related to stakeholders can re-monitor and analyze indicators.This allows for the addition or removal of third-tier indicators,adjustment of indicator weights,optimization of indicator content,precision in mea-suring indicators,and improvement of the performance evaluation effectiveness of level-3 public hospitals.

Objective:To investigate and summarize pediatric patients with severe Mycoplasma pneumoniae pneumonia (MPP) presenting with varied clinical and chest imaging features in order to guide the individualized treatment. Methods:This was a retrospective cohort study. Medical records of clinical, imaging and laboratory data of 505 patients with MPP who were admitted to the Department Ⅱ of Respirology Center, Beijing Children′s Hospital, Capital Medical University from January 2016 to October 2023 and met the enrollment criteria were included. They were divided into severe group and non-severe group according to whether lower airway obliterans was developed. The clinical and chest imaging features of the two groups were analyzed. Those severe cases with single lobe ≥2/3 consolidation (lobar consolidation) were further divided into subtype lung-necrosis and subtype non-lung-necrosis based on whether lung necrosis was developed. Comparison on the clinical manifestations, bronchoscopic findings, whole blood C-reactive protein (CRP) and other inflammatory indicators between the two subtypes was performed. Comparisons between two groups were achieved using independent-sample t-test, nonparametric test or chi-square test. Univariate receiver operating characteristic (ROC) curve analyses were performed on the indicators such as CRP of the two subtypes. Results:Of the 505 cases, 254 were male and 251 were female. The age of the onset was (8.2±2.9) years. There were 233 severe cases, among whom 206 were with lobar consolidation and 27 with diffuse bronchiolitis. The other 272 belonged to non-severe cases, with patchy, cloudy infiltrations or single lobe <2/3 uneven consolidation or localized bronchiolitis. Of the 206 cases (88.4%) severe cases with lobar consolidation, 88 harbored subtype lung-necrosis and 118 harbored subtype non-lung-necrosis. All 206 cases (100.0%) presented with persistent high fever, among whom 203 cases (98.5%) presented with inflammatory secretion obstruction and plastic bronchitis under bronchoscopy. Of those 88 cases with subtype lung-necrosis, there were 42 cases (47.7%) with dyspnea and 39 cases (44.3%) with moderate to massive amount of pleural effusion. There were 35 cases (39.8%) diagnosed with lung embolism during the disease course, of which other 34 cases (38.6%) were highly suspected. Extensive airway mucosal necrosis was observed in 46 cases (52.3%), and the level of their whole blood CRP was significantly higher than that of subtype non-lung-necrosis (131.5 (91.0, 180.0) vs. 25.5 (12.0, 43.1) mg/L, U=334.00, P<0.001). They were regarded as subtype "lung consolidation-atelectasis-necrosis". Of those 118 cases with subtype non-lung-necrosis, 27 cases (22.9%) presented with dyspnea and none were with moderate to massive amount of pleural effusion. Sixty-five cases (55.1%) presented with plastic bronchitis and localized airway mucosal necrosis was observed in 32 cases (27.1%). They were deemed as subtype "lung consolidation-atelectasis". ROC curve analyses revealed that whole blood CRP of 67.5 mg/L on the 6-10 th day of disease course exhibited a sensitivity of 0.96, a specificity of 0.89, and an area under the curve of 0.97 for distinguishing between these two subtypes among those with lobar consolidation. Conclusions:Pediatric patients with severe MPP present with lobar consolidation or diffuse bronchiolitis on chest imaging. Those with lobar consolidation harbor 2 subtypes as "lung consolidation-atelectasis-necrosis" and "lung consolidation-atelectasis". Whole blood CRP of 67.5 mg/L can be applied as an early discriminating indicator to discriminate between these two subtypes.

Objective It explores the importance and effectiveness perception of 55 third-tier indicators in the cur-rent performance evaluation system.Methods From the perspective of those being assessed,it employs survey ques-tionnaires,Importance Performance Analysis(IPA),and focus group interviews to conduct research on the impor-tance and effectiveness perception.Results The overall perception of the importance and effectiveness of third-tier in-dicators is relatively high,and the performance evaluation indicator system can effectively assess the development level of level-3 public hospitals.There is a general discrepancy between the perception of importance and effective-ness.Some third-tier indicators face issues of insufficient perception of both importance and effectiveness.Conclu-sion Performance evaluation policy formulation based on the implementation of policies and after excluding the scores of indicators closely related to stakeholders can re-monitor and analyze indicators.This allows for the addition or removal of third-tier indicators,adjustment of indicator weights,optimization of indicator content,precision in mea-suring indicators,and improvement of the performance evaluation effectiveness of level-3 public hospitals.

Objective It explores the importance and effectiveness perception of 55 third-tier indicators in the cur-rent performance evaluation system.Methods From the perspective of those being assessed,it employs survey ques-tionnaires,Importance Performance Analysis(IPA),and focus group interviews to conduct research on the impor-tance and effectiveness perception.Results The overall perception of the importance and effectiveness of third-tier in-dicators is relatively high,and the performance evaluation indicator system can effectively assess the development level of level-3 public hospitals.There is a general discrepancy between the perception of importance and effective-ness.Some third-tier indicators face issues of insufficient perception of both importance and effectiveness.Conclu-sion Performance evaluation policy formulation based on the implementation of policies and after excluding the scores of indicators closely related to stakeholders can re-monitor and analyze indicators.This allows for the addition or removal of third-tier indicators,adjustment of indicator weights,optimization of indicator content,precision in mea-suring indicators,and improvement of the performance evaluation effectiveness of level-3 public hospitals.

Objective It explores the importance and effectiveness perception of 55 third-tier indicators in the cur-rent performance evaluation system.Methods From the perspective of those being assessed,it employs survey ques-tionnaires,Importance Performance Analysis(IPA),and focus group interviews to conduct research on the impor-tance and effectiveness perception.Results The overall perception of the importance and effectiveness of third-tier in-dicators is relatively high,and the performance evaluation indicator system can effectively assess the development level of level-3 public hospitals.There is a general discrepancy between the perception of importance and effective-ness.Some third-tier indicators face issues of insufficient perception of both importance and effectiveness.Conclu-sion Performance evaluation policy formulation based on the implementation of policies and after excluding the scores of indicators closely related to stakeholders can re-monitor and analyze indicators.This allows for the addition or removal of third-tier indicators,adjustment of indicator weights,optimization of indicator content,precision in mea-suring indicators,and improvement of the performance evaluation effectiveness of level-3 public hospitals.

Objective It explores the importance and effectiveness perception of 55 third-tier indicators in the cur-rent performance evaluation system.Methods From the perspective of those being assessed,it employs survey ques-tionnaires,Importance Performance Analysis(IPA),and focus group interviews to conduct research on the impor-tance and effectiveness perception.Results The overall perception of the importance and effectiveness of third-tier in-dicators is relatively high,and the performance evaluation indicator system can effectively assess the development level of level-3 public hospitals.There is a general discrepancy between the perception of importance and effective-ness.Some third-tier indicators face issues of insufficient perception of both importance and effectiveness.Conclu-sion Performance evaluation policy formulation based on the implementation of policies and after excluding the scores of indicators closely related to stakeholders can re-monitor and analyze indicators.This allows for the addition or removal of third-tier indicators,adjustment of indicator weights,optimization of indicator content,precision in mea-suring indicators,and improvement of the performance evaluation effectiveness of level-3 public hospitals.

Objective It explores the importance and effectiveness perception of 55 third-tier indicators in the cur-rent performance evaluation system.Methods From the perspective of those being assessed,it employs survey ques-tionnaires,Importance Performance Analysis(IPA),and focus group interviews to conduct research on the impor-tance and effectiveness perception.Results The overall perception of the importance and effectiveness of third-tier in-dicators is relatively high,and the performance evaluation indicator system can effectively assess the development level of level-3 public hospitals.There is a general discrepancy between the perception of importance and effective-ness.Some third-tier indicators face issues of insufficient perception of both importance and effectiveness.Conclu-sion Performance evaluation policy formulation based on the implementation of policies and after excluding the scores of indicators closely related to stakeholders can re-monitor and analyze indicators.This allows for the addition or removal of third-tier indicators,adjustment of indicator weights,optimization of indicator content,precision in mea-suring indicators,and improvement of the performance evaluation effectiveness of level-3 public hospitals.

Objective It explores the importance and effectiveness perception of 55 third-tier indicators in the cur-rent performance evaluation system.Methods From the perspective of those being assessed,it employs survey ques-tionnaires,Importance Performance Analysis(IPA),and focus group interviews to conduct research on the impor-tance and effectiveness perception.Results The overall perception of the importance and effectiveness of third-tier in-dicators is relatively high,and the performance evaluation indicator system can effectively assess the development level of level-3 public hospitals.There is a general discrepancy between the perception of importance and effective-ness.Some third-tier indicators face issues of insufficient perception of both importance and effectiveness.Conclu-sion Performance evaluation policy formulation based on the implementation of policies and after excluding the scores of indicators closely related to stakeholders can re-monitor and analyze indicators.This allows for the addition or removal of third-tier indicators,adjustment of indicator weights,optimization of indicator content,precision in mea-suring indicators,and improvement of the performance evaluation effectiveness of level-3 public hospitals.