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.

Objective A feasible and stable mouse model of thoracic aortic dissection(TAD)combined with acute lung injury(ALI)was established using β-aminopropionitrile monofumarate(BAPN)1 g/(kg·d)administered in drinking water.The mouse model of TAD combined with acute lung injury(ALI)was established to provide a rational animal model to study TAD combined with ALI.Methods Forty-five SPF-grade 3-week-old C57BL/6J male mice were selected and randomly allocated to a CON group(normal dietary water;15 mice)or BAPN group(administration in sterile water at 1 g/(kg·d);30 mice)for 4 weeks.During the experimental period,the general condition and modeling rate of mice were observed.TAD model mice were validated,and the BAPN group was divided into TAD and non-TAD groups by measuring the maximum diameter of the thoracic aorta and HE staining of aortic tissues.HE pathological staining,the wet/dry weight(W/D)ratio,total protein level in bronchioalveolar lavage fluid(BALF),and interleukin(IL)-1 β,IL-6,and tumor necrosis factor-α(TNF-α)in BALF)were used to validate the TAD combined ALI model in mice.Results BAPN treatment significantly delayed the increase in body mass and water intake of mice.Compared with CON and non-TAD groups,the maximum diameter of the thoracic aorta of mice in the TAD group was significantly thickened(P＜0.05).HE staining of the aorta showed significant thickening of the middle aortic layer,and the structure of the aortic wall was damaged and disordered.HE staining of lung tissues showed significant interstitial edema and inflammatory exudation accompanied by enlargement of alveolar lumen,alveolar wall epithelial exfoliation and hyaline membrane formation,and a significant increase in the pathological scores of lung injury(P＜0.05).Total protein levels and expression of IL-1β,IL-6,and TNF-α in lung tissue,W/D ratio,and BALF were also significantly increased(P＜0.05),whereas no significant difference was observed in the above indexes between the other two groups.Conclusions A mouse model of thoracic aortic dissection combined with acute lung injury can be established by BAPN administration in drinking water.

Objective:To analyze the clinical phenotypes and TSC1/TSC2 gene variations in 52 children with tuberous sclerosis complex. Methods:The clinical data of 59 children with tuberous sclerosis complex hospitalized in Linyi People′s Hospital between January 2017 and October 2022 were collected. The analysis of TSC1 and TSC2 gene variations on main family members was performed, and then bioinformatics analysis followed. The positive children were divided into TSC1 gene group and TSC2 gene group, and the difference of clinical characteristics between the two groups was analyzed. Results:Among 59 children, 52 cases were detected TSC1/ TSC2 gene variations (17 cases in the TSC1 gene group and 35 cases in the TSC2 gene group). Of the 52 children, 28 (53.8%) were male, 24 were female (46.2%); 17 (32.7%) were familial cases (10 with TSC1 gene variations and 7 with TSC2 gene variations), 35 (67.3%) were sporadic cases; 46 (88.5%) had hypomelanotic macules, 13 (25.0%) had facial angiofibromas, 5 (9.6%) had shagreen patches, 49 (94.2%) had subependymal nodules/calcifications, 47 (90.4%) had cortical nodules, 2 (3.8%) had subependymal giant cell astrocytomas, 39 (75.0%) had intellectual/developmental disabilities, 49 (94.2%) had epileptic seizures, 8 (15.4%) had cardiac rhabdomyomas, 9 (17.3%) had renal angiomyolipomas, and 4 (7.7%) had retinal hamartomas. Of the 52 children, 49 variations were detected, including 4 large fragment deletion/duplication variations, and 45 point variations; 41 pathogenic variations, 7 likely pathogenic variations, and 1 variation of uncertain significance. In this study, 16 point mutations and 1 large fragment duplication mutation which had not been reported at home and abroad, and 3 high-frequency mutation sites (p.Arg692 *, p.Arg228 *, and p.Arg1200Try) were found. There was a statistically significant difference in the proportion of familial cases [10/17 vs 7/35(20%), χ2=7.838, P=0.005], median onset age of epilepsy [38.0(0.5-134.0) months vs 8.0(0.1-63.0) months, Z=3.506 , P<0.001] and the incidence of developmental retardation/intellectual impairment [8/17 vs 31/35(88.6%), χadj2=8.423, P=0.004] between the TSC1 gene and TSC2 gene groups. Conclusions:Tuberous sclerosis compiex has widespread phenotypes, can affect every body system, especially the skin and nervous system. The pathogenic gene is TSC1/ TSC2. The TSC1 gene group has more familial cases. The TSC2 gene group has an earlier onset age of epilepsy and a higher incidence of developmental retardation/intellectual impairment. In this study, 16 novel point mutations, 1 novel large fragment duplication mutation, and 3 hotspot mutations were identified, expanding the gene variation spectrum of tuberous sclerosis complex.

The 20th National Congress report proposed the most important and core strategic path of national governance:Chinese modernization.Under the guidance of the top-level design,the healthcare security system needs to find a new paradigm of healthcare security governance under the Chinese modernization that is both in line with Chinese characteristics and the basic laws and characteristics of the world's sanitary resources.Combined with the 20th National Congress report,the medical reform tasks of"promoting the development and governance of medical services,medical insurance and pharmaceutical synergy"and"promoting the inheritance of Traditional Chinese Medicine"are required to learn from the international"disproportionate share"health resources compensation system.From the perspective of necessity and adaptability,it explore the Traditional Chinese Medicine(TCM)disproportionate share mechanism of medical insurance,in order to maximize the realization of the strategic purchasing goal of health insurance and to provide a systematic,standardized and sustainable modernized Chinese health insurance model for the continuous support of TCM medicine special diagnosis and treatment with medical insurance resources.

Under the structural pressure of aging acceleration and increased chronic disease burden,in order to implement the reform tasks of"promoting healthcare,insurance and pharmaceutical sectors coordinated develop-ment and governance"proposed by the 20th National Congress of the Communist Party of China,it is urgent to build a medical insurance governance system that is adapted to the"Synergistic goverance on healthcare,insurance and pharmaceutical sectors".In order to break the single,fragmented,and passive medical insurance management methods in the past,according to the theoretical framework of system theory,it proposes the"chain-net"gover-nance system of hospital medical insurance built by the policy responsibility chain,information process chain,col-laborative consensus chain,inspection evaluation chain,and performance value chain,and analyzes,the implemen-tation path,necessity and completeness and support elements of this system.

The 20th National Congress report proposed the most important and core strategic path of national governance:Chinese modernization.Under the guidance of the top-level design,the healthcare security system needs to find a new paradigm of healthcare security governance under the Chinese modernization that is both in line with Chinese characteristics and the basic laws and characteristics of the world's sanitary resources.Combined with the 20th National Congress report,the medical reform tasks of"promoting the development and governance of medical services,medical insurance and pharmaceutical synergy"and"promoting the inheritance of Traditional Chinese Medicine"are required to learn from the international"disproportionate share"health resources compensation system.From the perspective of necessity and adaptability,it explore the Traditional Chinese Medicine(TCM)disproportionate share mechanism of medical insurance,in order to maximize the realization of the strategic purchasing goal of health insurance and to provide a systematic,standardized and sustainable modernized Chinese health insurance model for the continuous support of TCM medicine special diagnosis and treatment with medical insurance resources.

Under the structural pressure of aging acceleration and increased chronic disease burden,in order to implement the reform tasks of"promoting healthcare,insurance and pharmaceutical sectors coordinated develop-ment and governance"proposed by the 20th National Congress of the Communist Party of China,it is urgent to build a medical insurance governance system that is adapted to the"Synergistic goverance on healthcare,insurance and pharmaceutical sectors".In order to break the single,fragmented,and passive medical insurance management methods in the past,according to the theoretical framework of system theory,it proposes the"chain-net"gover-nance system of hospital medical insurance built by the policy responsibility chain,information process chain,col-laborative consensus chain,inspection evaluation chain,and performance value chain,and analyzes,the implemen-tation path,necessity and completeness and support elements of this system.

The 20th National Congress report proposed the most important and core strategic path of national governance:Chinese modernization.Under the guidance of the top-level design,the healthcare security system needs to find a new paradigm of healthcare security governance under the Chinese modernization that is both in line with Chinese characteristics and the basic laws and characteristics of the world's sanitary resources.Combined with the 20th National Congress report,the medical reform tasks of"promoting the development and governance of medical services,medical insurance and pharmaceutical synergy"and"promoting the inheritance of Traditional Chinese Medicine"are required to learn from the international"disproportionate share"health resources compensation system.From the perspective of necessity and adaptability,it explore the Traditional Chinese Medicine(TCM)disproportionate share mechanism of medical insurance,in order to maximize the realization of the strategic purchasing goal of health insurance and to provide a systematic,standardized and sustainable modernized Chinese health insurance model for the continuous support of TCM medicine special diagnosis and treatment with medical insurance resources.

Under the structural pressure of aging acceleration and increased chronic disease burden,in order to implement the reform tasks of"promoting healthcare,insurance and pharmaceutical sectors coordinated develop-ment and governance"proposed by the 20th National Congress of the Communist Party of China,it is urgent to build a medical insurance governance system that is adapted to the"Synergistic goverance on healthcare,insurance and pharmaceutical sectors".In order to break the single,fragmented,and passive medical insurance management methods in the past,according to the theoretical framework of system theory,it proposes the"chain-net"gover-nance system of hospital medical insurance built by the policy responsibility chain,information process chain,col-laborative consensus chain,inspection evaluation chain,and performance value chain,and analyzes,the implemen-tation path,necessity and completeness and support elements of this system.

The 20th National Congress report proposed the most important and core strategic path of national governance:Chinese modernization.Under the guidance of the top-level design,the healthcare security system needs to find a new paradigm of healthcare security governance under the Chinese modernization that is both in line with Chinese characteristics and the basic laws and characteristics of the world's sanitary resources.Combined with the 20th National Congress report,the medical reform tasks of"promoting the development and governance of medical services,medical insurance and pharmaceutical synergy"and"promoting the inheritance of Traditional Chinese Medicine"are required to learn from the international"disproportionate share"health resources compensation system.From the perspective of necessity and adaptability,it explore the Traditional Chinese Medicine(TCM)disproportionate share mechanism of medical insurance,in order to maximize the realization of the strategic purchasing goal of health insurance and to provide a systematic,standardized and sustainable modernized Chinese health insurance model for the continuous support of TCM medicine special diagnosis and treatment with medical insurance resources.