Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To develop a quality control model for anal sphincter ultrasound images and validate its diagnostic performance across multiple centers.Methods:A retrospective analysis was conducted on anal sphincter ultrasound images from seven medical centers in China between May 2019 and June 2022. A total of 7 040 images from 3 116 patients were included and divided into a training set（4 912 images）and a validation set（2 128 images）. The images were classified as standard or non-standard images by three experts. Three models were developed based on different image feature extraction methods：a single-branch model，a multi-branch weighted model，and a multi-branch ensemble model. The diagnostic performance of each model was evaluated using the area under the ROC curve（AUC），sensitivity，specificity，accuracy，positive predictive value，and negative predictive value，respectively. The optimal model was selected and compared with the performance of 4 doctors with varying experience levels. Sixty days later，the images with the assistance of the model's output were reassessed by the doctors to evaluate its impact on manual quality control.Results:① Among the 3 models，the multi-branch ensemble model demonstrated the highest AUC and sensitivity，with an AUC of 0.966（95% CI=0.958 - 0.974），a sensitivity of 91.83%，and a specificity of 91.41%. This model was named M quality. ② M quality's AUC was slightly lower than that of Senior A and B（0.966 vs. 0.976，0.976，and P<0.05），its sensitivity was slightly lower than that of Senior A（91.83% vs. 95.61%， P<0.001）but comparable to Senior B（91.83% vs. 92.89%， P=0.315），its specificity was slightly lower than Senior A and B（91.41% vs. 94.44%，98.18%，and P<0.05）. However，M quality significantly outperformed Junior A and B in AUC and sensitivity（AUC：0.966 vs. 0.850，0.818；sensitivity：91.83% vs. 84.90%，61.46%；all P<0.001），its specificity was higher than that of Junior A（91.41% vs. 80.28%， P<0.001）but lower than that of Junior B（91.41% vs. 95.96%， P<0.001）. ③ With model assistance，Senior B's sensitivity（92.89% vs. 94.20%， P=0.001）and Senior A's specificity（94.44% vs. 96.56%， P<0.001）improved significantly. Junior A and B showed significant improvements in AUC and sensitivity（AUC：0.931 vs. 0.850，0.914 vs. 0.818；sensitivity：91.83% vs. 84.90%，89.53% vs. 61.46%；all P<0.001）. After model assistance，Junior A's specificity increased（93.62% vs. 80.28%， P<0.001），while Junior B's specificity decreased（91.60% vs. 95.96%， P=0.013）. Conclusions:This study develops a quality control model for anal sphincter ultrasound images with robust diagnostic performance，approaching the level of seniors. The model significantly enhances the image quality assessment capabilities of juniors，demonstrating promising clinical application potential.

Aim To study the difference in hepatotox-icity of psoralen on normal rats and Yin-deficiency rats from the perspective of lipid metabolism,so as to help explain the mechanism of psoralen cautiously used in patients with Yin deficiency recorded in ancient books.Methods SD rats were randomly divided into the nor-mal control group(carboxymethyl cellulose-Na,CMC-Na),normal administration group(CMC-Na+psor-alen),Yin-deficiency control group(CMC-Na+thy-roxine)and Yin-deficiency administration group(CMC-Na+thyroxine+psoralen).The model of Yin-deficiency was established by thyroxine(1 mg·kg-1)for ten days,and then psoralen(200 mg·kg-1)was given for three days.The serum indexes related to liver injury were detected by automatic biochemical analy-zer,the morphological changes of liver tissue were ob-served using HE and oil red O staining,and the relative transcription levels of lipid metabolism related enzymes and mRNA of transporter and endoplasmic reticulum stress related factors were detected using Real-time PCR.Results After intragastric administration of psoralen for three days,compared with the normal group,the levels of serum alanine aminotransferase(ALT),aspartate transaminase(AST),total bile acid(TBA)and triglyeride(TG)in Yin deficiency group increased more significantly,while TC,ALB and TP de-creased more significantly,and liver HE and oil red O staining showed more obvious lipid degeneration.TG synthesis factors adrenocortical carcinoma(ACC),fatty acid synthase(FASN)and sterolregulatory element binding protein-1(SREBP-1)were down-regulated more significantly,TG transport factors mili-total pro-tein(MTP)and lipoprotein pipase(LPL)were down-regulated more evidently,fatty acid β-oxidation related factors carnitine palmitoyltransferase 1A(CPT1A),carnitine/organic cation transporter 2(OCTN2)and peroxisome proliferators-activated receptors-alpha(PPARα)were down-regulated more apparently,TC transporter adenosine triphosphate binding cassette transporter G8(ABCG8)and bile acid receptor farne-soid X receptor(FXR)were down-regulated more ob-viously,and endoplasmic reticulum stress factor activa-ting transcription factor 4(ATF4)was up-regulated more significantly.Conclusions Psoralen can cause more severe hepatotoxicity in Yin deficiency rats than that in normal administration group,and its mechanism may be related to the disorder of hepatic lipid metabo-lism,aggravation of hepatic cholestasis and steatosis,and activation of endoplasmic reticulum stress re-sponse.

Aim To study the difference in hepatotox-icity of psoralen on normal rats and Yin-deficiency rats from the perspective of lipid metabolism,so as to help explain the mechanism of psoralen cautiously used in patients with Yin deficiency recorded in ancient books.Methods SD rats were randomly divided into the nor-mal control group(carboxymethyl cellulose-Na,CMC-Na),normal administration group(CMC-Na+psor-alen),Yin-deficiency control group(CMC-Na+thy-roxine)and Yin-deficiency administration group(CMC-Na+thyroxine+psoralen).The model of Yin-deficiency was established by thyroxine(1 mg·kg-1)for ten days,and then psoralen(200 mg·kg-1)was given for three days.The serum indexes related to liver injury were detected by automatic biochemical analy-zer,the morphological changes of liver tissue were ob-served using HE and oil red O staining,and the relative transcription levels of lipid metabolism related enzymes and mRNA of transporter and endoplasmic reticulum stress related factors were detected using Real-time PCR.Results After intragastric administration of psoralen for three days,compared with the normal group,the levels of serum alanine aminotransferase(ALT),aspartate transaminase(AST),total bile acid(TBA)and triglyeride(TG)in Yin deficiency group increased more significantly,while TC,ALB and TP de-creased more significantly,and liver HE and oil red O staining showed more obvious lipid degeneration.TG synthesis factors adrenocortical carcinoma(ACC),fatty acid synthase(FASN)and sterolregulatory element binding protein-1(SREBP-1)were down-regulated more significantly,TG transport factors mili-total pro-tein(MTP)and lipoprotein pipase(LPL)were down-regulated more evidently,fatty acid β-oxidation related factors carnitine palmitoyltransferase 1A(CPT1A),carnitine/organic cation transporter 2(OCTN2)and peroxisome proliferators-activated receptors-alpha(PPARα)were down-regulated more apparently,TC transporter adenosine triphosphate binding cassette transporter G8(ABCG8)and bile acid receptor farne-soid X receptor(FXR)were down-regulated more ob-viously,and endoplasmic reticulum stress factor activa-ting transcription factor 4(ATF4)was up-regulated more significantly.Conclusions Psoralen can cause more severe hepatotoxicity in Yin deficiency rats than that in normal administration group,and its mechanism may be related to the disorder of hepatic lipid metabo-lism,aggravation of hepatic cholestasis and steatosis,and activation of endoplasmic reticulum stress re-sponse.

Objective:To develop a quality control model for anal sphincter ultrasound images and validate its diagnostic performance across multiple centers.Methods:A retrospective analysis was conducted on anal sphincter ultrasound images from seven medical centers in China between May 2019 and June 2022. A total of 7 040 images from 3 116 patients were included and divided into a training set（4 912 images）and a validation set（2 128 images）. The images were classified as standard or non-standard images by three experts. Three models were developed based on different image feature extraction methods：a single-branch model，a multi-branch weighted model，and a multi-branch ensemble model. The diagnostic performance of each model was evaluated using the area under the ROC curve（AUC），sensitivity，specificity，accuracy，positive predictive value，and negative predictive value，respectively. The optimal model was selected and compared with the performance of 4 doctors with varying experience levels. Sixty days later，the images with the assistance of the model's output were reassessed by the doctors to evaluate its impact on manual quality control.Results:① Among the 3 models，the multi-branch ensemble model demonstrated the highest AUC and sensitivity，with an AUC of 0.966（95% CI=0.958 - 0.974），a sensitivity of 91.83%，and a specificity of 91.41%. This model was named M quality. ② M quality's AUC was slightly lower than that of Senior A and B（0.966 vs. 0.976，0.976，and P<0.05），its sensitivity was slightly lower than that of Senior A（91.83% vs. 95.61%， P<0.001）but comparable to Senior B（91.83% vs. 92.89%， P=0.315），its specificity was slightly lower than Senior A and B（91.41% vs. 94.44%，98.18%，and P<0.05）. However，M quality significantly outperformed Junior A and B in AUC and sensitivity（AUC：0.966 vs. 0.850，0.818；sensitivity：91.83% vs. 84.90%，61.46%；all P<0.001），its specificity was higher than that of Junior A（91.41% vs. 80.28%， P<0.001）but lower than that of Junior B（91.41% vs. 95.96%， P<0.001）. ③ With model assistance，Senior B's sensitivity（92.89% vs. 94.20%， P=0.001）and Senior A's specificity（94.44% vs. 96.56%， P<0.001）improved significantly. Junior A and B showed significant improvements in AUC and sensitivity（AUC：0.931 vs. 0.850，0.914 vs. 0.818；sensitivity：91.83% vs. 84.90%，89.53% vs. 61.46%；all P<0.001）. After model assistance，Junior A's specificity increased（93.62% vs. 80.28%， P<0.001），while Junior B's specificity decreased（91.60% vs. 95.96%， P=0.013）. Conclusions:This study develops a quality control model for anal sphincter ultrasound images with robust diagnostic performance，approaching the level of seniors. The model significantly enhances the image quality assessment capabilities of juniors，demonstrating promising clinical application potential.

α7 nicotinic acetylcholine receptor(α7nAChR)is widely expressed in the central nervous system and immune system,and plays a neuro-immunoregulatory role.On the one hand,α7nAChR is involved in the transmission of neurotransmitters,the conduction of excitatory signals and the maintenance of synaptic plasticity,which is of great significance for maintaining the normal and stable neurocognitive function.On the other hand,as an important part of the cholinergic anti-inflammatory pathway,α7nAChR is involved in the regulation of physiological and pathological processes such as inflammatory response,oxidative stress,apoptosis and autophagy in the central system,and plays an immunomodulatory and neuroprotective role,thus being potential target for improving perioperative neurocognitive function.This article reviews the biological characteristics of α7nAChR and its effect on perioperative neurocognitive function,in order to provide ideas and methods for clinical improvement of perioperative neurocognitive function in surgical patients.

Objective To explore the application value of vesicourethral anastomosis with maximal urethral length preservation(MULP)and bladder neck preservation(BNP)in laparoscopic radical prostatectomy(LRP)or robot-assisted laparoscopic radical prostatectomy(RALP)for high-risk prostate cancer(HRPC)in terms of early urinary continence and oncology.Methods Clinical data of 23 HRPC patients who underwent LRP(including RALP)with MULP and BNP in our hospital during May 2022 and Jan.2024 were retrospectively analyzed.Patients'basic information,surgical parameters,postoperative complications,oncological outcomes and urinary incontinence were collected and analyzed.Results All operations were completed successfully without conversion to open surgery.The operation time was(108±31)min,average blood loss(112±45)mL,hospital stay(5.5±1.5)days,urethral catheterization time(12.6±1.8)days,and no patient received blood transfusion during operation.The urinary continence rates at the time of catheter removal,and at 1,3,and 6 months after surgery were 39.1％,65.2％,73.9％,and 91.3％,respectively.Two patients had positive margins,both of which were at the neurovascular bundle.No patient developed surgery-related complications,urinary obstruction or fistula after surgery.Conclusion Vesicourethral anastomosis with MULP and BNP in LRP for HRPC can effectively improve patients'early urinary continence rate and postoperative quality of life without increasing the oncological risk.

Lipopolysaccharides (LPS) are major outer membrane components of Gram-negative bacteria. Unlike most Gram-negative bacteria, Acinetobacter baumannii can still survive and acquire polymyxin resistance after complete loss of LPS. Previous studies of LPS-deficient Acinetobacter baumannii mostly focused on LPS-deficient strains induced by polymyxin, whose background was complex and unstable. To investigate LPS loss-mediated polymyxin resistant-Acinetobacter baumannii, this study constructed a stable and clear background LPS-deficient strain by knocking out lpxC gene in Acinetobacter baumannii ATCC 19606 with CIRSPR/Cas9, and then studied the phenotypic changes of the lpxC-deficient strain including morphology, growth rate, antibiotic susceptibility, virulence, membrane permeability, and membrane potential. Animal experiments were approved by the Animal Care and Welfare Committee Institute of Medicinal Biotechnology, CAMS and PUMC (approval number: IMB-20240119D₉). The results indicated that the lpxC gene of Acinetobacter baumannii ATCC 19606 was successfully knocked out. After losing the lpxC, the strain underwent the morphological change from rod-shaped to spherical. Furthermore, it leads to reduced growth rate, enhanced membrane permeability, decreased membrane potential, lower virulence, and increased antibiotic susceptibility to β-lactams, quinolones, aminoglycosides, macrolides, glycopeptides. The lpxC deletion results in significant changes in membrane homeostasis and adaptability of Acinetobacter baumannii. Understanding the phenotypic changes of colistin-resistant Acinetobacter baumannii mediated by LPS loss is useful for exploring the resistance mechanism of Acinetobacter baumannii and developing new therapeutic strategies.

Objective: To investigate the clinicopathological features, treatment and prognosis of gastric intermediate-risk gastrointestinal stromal tumor (GIST), so as to provide a reference for clinical management and further research. Methods: A retrospective observational study of patients with gastric intermediate-risk GIST, who underwent surgical resection between January 1996 and December 2019 at Zhongshan Hospital of Fudan University, was carried out. Results: Totally, 360 patients with a median age of 59 years were included. There were 190 males and 170 females with median tumor diameter of 5.9 cm. Routine genetic testing was performed in 247 cases (68.6%, 247/360), and 198 cases (80.2%) showed KIT mutation, 26 cases (10.5%) showed PDGFRA mutation, and 23 cases were wild-type GIST. According to "Zhongshan Method"(including 12 parameters), there were 121 malignant and 239 non-malignant cases. Complete follow-up data were available in 241 patients; 55 patients (22.8%) received imatinib therapy, 10 patients (4.1%) experienced tumor progression, and one patient (PDGFRA mutation, 0.4%) died. Disease-free survival (DFS) and overall survival rate at 5 years was 96.0% and 99.6%, respectively. Among the intermediate-risk GIST, there was no difference in DFS between the overall population, KIT mutation, PDGFRA mutation, wild-type, non-malignant and malignant subgroups (all P>0.05). However, the non-malignancy/malignancy analysis showed that there were significant differences in DFS among the overall population (P<0.01), imatinib treatment group (P=0.044) and no imatinib treatment group (P<0.01). Adjuvant imatinib resulted in potential survival benefit for KIT mutated malignant and intermediate-risk GIST in DFS (P=0.241). Conclusions: Gastric intermediate-risk GIST shows a heterogeneous biologic behavior spectrum from benign to highly malignant. It can be further classified into benign and malignant, mainly nonmalignant and low-grade malignant. The overall disease progression rate after surgical resection is low, and real-world data show that there is no significant benefit from imatinib treatment after surgery. However, adjuvant imatinib potentially improves DFS of intermediate-risk patients with tumors harboring KIT mutation in the malignant group. Therefore, a comprehensive analysis of gene mutations in benign/malignant GIST will facilitate improvements in therapeutic decision-making.
Male ; Female ; Humans ; Middle Aged ; Gastrointestinal Stromal Tumors/surgery* ; Retrospective Studies ; Antineoplastic Agents/therapeutic use* ; Prognosis ; Imatinib Mesylate/therapeutic use* ; Mutation ; Proto-Oncogene Proteins c-kit/genetics*

As a recognized rare and highly fatal disease, hereditary angioedema (HAE) is difficult to diagnose and characterized by recurrent edema involving the head, limbs, genitals and larynx, etc. Diagnosis of HAE is not difficult. However, low incidence and lack of clinical characteristics lead to difficulty of doctors on timely diagnosis and correct intervention for HAE patients. Therefore, it is crucial to improve the awareness of this disease and prevent its recurrence. for HAE patients. In view of absent cognition of doctors and the general public on HAE, patients often suffer from sudden death or become disabled due to laryngeal edema which cannot be treated in time. Thus, based on the Internet mobile terminal platform, the team set up an all-day rapid emergency response system which is provided for HAE patients by setting up "one-click help". The aim is to offer optimization on overall management of HAE and designed the intelligent follow-up management to provide timely assistance and specialized suggestion for patients with acute attacks.
Humans ; Angioedemas, Hereditary/drug therapy*