Background Atmospheric fine particulate matter (PM_2.5) can disrupt the metabolic homeostasis of the liver and accelerate the progression of liver diseases, but there are few studies on the effects of sub-chronic PM_2.5 exposure on the liver metabolome. Objectives To investigate the effects of sub-chronic exposure to concentrated PM_2.5 on hepatic metabolomics in mice by liquid chromatography-mass spectrometry (LC-MS), and to identify potentially affected metabolites and metabolic pathways. Methods Twelve male C57BL/6J (6 weeks old) mice were randomly divided into two groups: a concentrated PM_2.5 exposure group and a clean air exposure group. The mice were exposed to concentrated PM_2.5 using the "Shanghai Meteorological and Environmental Animal Exposure System" at Fudan University. The exposure duration was 8 h per day, 6 d per week, for a total of 8 weeks. The mice's liver tissues were collected 24 h after the completion of exposure. LC-MS was performed to assess changes in the hepatic metabolome. Orthogonal partial least squares discriminant analysis and t-test were employed to identify differentially regulated metabolites between the two groups under the conditions of variable important in projection (VIP)≥1.0 and P<0.05. Metabolic pathway enrichment analysis was performed using MetaboAnalyst 5.0 software and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results A total of 297 differentially regulated metabolites were identified between the concentrated PM_2.5 exposure group and the clean air group. Among these metabolites, 142 were upregulated and 155 were downregulated. A total of 38 metabolic pathways were altered, with 7 pathways showing significant perturbation (P<0.05). These pathways involved amino acid metabolism, glucose metabolism, nucleotide metabolism, as well as cofactor and vitamin metabolism. The 7 significant metabolic pathways were pantothenic acid and coenzyme A biosynthesis; purine metabolism; amino sugar and nucleotide sugar metabolism; arginine biosynthesis; alanine, aspartate and glutamate metabolism; aminoacyl-tRNA biosynthesis; and fructose and mannose metabolism. Conclusion The results from metabolomics analysis suggest that sub-chronic exposure to PM_2.5 may disrupt hepatic energy metabolism and induce oxidative stress damage. Aspartic acid, succinic acid, ornithine, fumaric acid, as well as purine and xanthine derivatives, were identified as potential early biomarkers of hepatic response to sub-chronic PM_2.5 exposure.

Morita therapy has been bom for more than 100 years.Inpatient Morita therapy is highly oper-able and easy to master.It can improve many refractory neuroses through four-stage treatment.But more neuroses are treated in outpatient clinics,and Morita therapy cannot be used in hospitalized patients.Therefore,the formula-tion of expert opinions on outpatient operations is particularly important.This paper is based on domestic and for-eign references,and after many discussions by domestic Morita therapy experts,and then drew up the first version of the expert opinions on operation of outpatient Morita therapy.Meanwhile the operation rule of Morita therapy in three stages of outpatient treatment was formulated:in the etiological analysis stage,under the theoretical guidance of Morita therapy,analyze the pathogenic factors,to improve treatment compliance and reduce resistance;during the operating stage,guide patients to engage in constructive and meaningful actions,realizing the achievement of letting nature take its course principle;in the cultivating character and enriching life stage,pay attention to positive infor-mation,expanding the scope and content of actions,improving the ability to adapt to complex life,and preventing recurrence caused by insufficient abilities.It will lay a foundation for the promotion of Morita therapy in domestic outpatient clinics,so that more patients with neurosis and other psychological diseases could receive characteristic Morita therapy treatment in outpatient clinics.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

OBJECTIVE To mine and analyze the adverse drug events （ADE） signals of two camptothecin topoisomerase 1 inhibitors， i.e. irinotecan and topotecan， and to provide reference for clinical medication safety. METHODS Based on the U.S. Food and Drug Administration Adverse Event Reporting System （FAERS） database， ADE report data for the aforementioned two drugs were extracted from January 1， 2004 to March 31， 2023. After processing the data， signal mining was conducted by using the reporting odds ratio in conjunction with the Bayesian confidence propagation neural network， followed by analysis. RESULTS A total of 14 738 relevant ADE reports were screened， among which 11 483 were associated with irinotecan and 3 255 with topotecan. The ADE reports for irinotecan were predominantly male， whereas for topotecan， they were predominantly female； the age of patients using the two drugs mainly concentrated in 45-＜75 years old. A total of 847 signals were detected， involving 24 system organ classes （SOCs）. Among them， 565 signals of irinotecan were detected， involving 24 SOCs， primarily concentrating on gastrointestinal disorders， general disorders and administration site conditions， blood and lymphatic system disorders； the most frequently reported ADE was diarrhea， and the ADE with the strongest signal intensity was cholinergic syndrome. A total of 282 signals of topotecan were detected， involving 22 SOCs， primarily concentrating on general disorders and administration site conditions， investigations， blood and lymphatic system disorders， and gastrointestinal disorders； the most frequently reported ADEs were death and anemia， and the ADE with the strongest signal intensity was febrile bone marrow aplasia. ADE signals for irinotecan such as metastatic colorectal cancer， peripheral sensory neuropathy， steatohepatitis， and those for topotecan such as iris atrophy， retinal degeneration， vitreous hemorrhage， were not documented in their respective drug instruction. CONCLUSIONS ADEs of irinotecan and topotecan primarily involve the digestive and hematologic systems， warranting close clinical monitoring. Cholinergic syndrome caused by irinotecan should be concerned. In addition， patients receiving irinotecan should also be monitored for ADE such as metastatic colorectal cancer， peripheral sensory neuropathy， steatohepatitis， and proteinuria； for patients using topotecan， enhanced surveillance of ocular diseases is recommended to ensure medication safety.

The prevalence of diabetes mellitus in China has recently been increasing year by year,and spontaneous skin ulcers in diabetic patients,as one of the most serious complications,often develop on the patient's extremities represented by foot ulcers.Due to the complexity and variety of its pathogenesis,it leads to poor clinical outcomes and difficulty in healing.Thus,pa-tients often face the risk of amputation and death.Therefore,the exploration of mechanisms of the vascular pathogenesis of diabetic delayed-healing wounds and targeted screening of therapeutic agents has become a current research hotspot.Herein,in this paper,we briefly review the role of impaired angiogenesis and vascular dysfunction in diabetic skin ulcers,and the research progress of classical hypoglycemic and natural compounds against vascular lesions is preliminarily summarized to provide a theoretical basis for effective clinical treatment.

Objective:To analyze the short-term clinical efficacy and safety of arsenic trioxide (ATO) combined with a modified N7 induction regimen in the treatment of children with high-risk neuroblastoma (NB).Methods:This study was a prospective, single-arm, multicenter phase Ⅱ clinical study. Sixty-seven high-risk NB children from eight units of Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Wuhan Children′s Hospital of Tongji Medical College of Huazhong University of Science and Technology, First Affiliated Hospital of Guangxi Medical University, Hainan General Hospital, Affiliated Hospital of Guangdong Medical University, Kunming Children′s Hospital, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, and Guangdong Provincial Agricultural Reclamation Center Hospital were enrolled from January 2019 to August 2023 and were treated with ATO combined with a modified N7 induction regimen. The efficacy and adverse effects at the end of induction chemotherapy were assessed and analyzed, and the differences in the clinical characteristics were further compared between the treatment-responsive and treatment-unresponsive groups by using the Fisher′s exact test.Results:Among 67 high-risk NB children, there were 40 males (60%) and 27 females (40%), with the age of disease onset of 3.5 (2.6, 4.8) years. Primary NB sites were mostly in retroperitoneum (including adrenal gland) (56/67, 84%) and the common metastases sites at initial diagnosis were distant lymph node in 25 cases (37%),bone in 48 cases (72%),bone marrow in 56 cases (84%) and intracalvarium in 3 cases (4%). MYCN gene amplification were detected in 28 cases (42%). At the end of induction, 33 cases (49%) achieved complete remission, 29 cases (43%) achieved partial remission, 1 case (1%) with stable disease, and 4 cases (6%) were assessed as progressive disease (PD). The objective remission rate was 93% (62/67) and the disease control rate was 94% (63/67). The percentage of central system metastases at the initial diagnosis was higher in the treatment-unresponsive group than in the treatment-responsive group (2/5 vs. 2% (1/62), P=0.013), whereas the difference in MYCN gene amplification was not statistically significant between two groups (3/5 vs.40% (25/62), P=0.786). Grade Ⅲ or higher adverse reactions during the induction chemotherapy period were myelosuppression occurred in 60 cases (90%), gastrointestinal symptoms occurred in 33 cases (49%), infections occurred in 20 cases (30%), hepatotoxicity occurred in 4 cases (6%), and cardiovascular toxicity occurred in 1 case (2%). There were no chemotherapy-related deaths. Conclusion:ATO combined with N7-modified induction regimen had a superiority in efficacy and safety, which deserved further promotion in clinical practice.

Aim To investigate the inhibition role and mechanism of adipose derived mesenchymal stem cell(ADMSC)exosomes(Exo)on adverse ventricular remodeling after myocardial infarction(MI).Methods The chan-ges of autophagy and inflammasomes phenotype of cardiac fibroblasts after H2O2 treatment were observed.MI rats were in-jected with an equal volume of normal saline,adipose derived mesenchymal stem cell exosomes(MSC-Exo)or fibroblast exosomes(MEF-Exo)via a tail vein.The expression of autophagy related 16 like protein 1(ATG16L1),autophagy re-lated protein 7(ATG7)and NOD-like receptor protein 3(NLRP3),inflammatory response,the degree of myocardial fi-brosis,and the cardiac function were observed in different groups.Results After treatment with H2O2 on cardiac fi-broblasts,the expressions of ATG16L1 and ATG7 were significantly decreased(P＜0.001),NLRP3 was significantly in-creased(P＜0.001),and the levels of inflammatory cytokines interleukin-1β(IL-1β)and IL-18 were significantly elevated(P＜0.001).After MI rats were intervened with MSC-Exo,the expressions of autophagy related proteins ATG16L1 and ATG7 were significantly up-regulated(P＜0.001),NLRP3 was significantly down-regulated(P＜0.001),serum IL-1β and IL-18 levels were significantly decreased(P＜0.001),fibrosis-related proteins collagen Ⅰ and Ⅲ were significantly reduced(P＜0.001),myocardial fibrosis was significantly relieved(P＜0.001),and cardiac function was sig-nificantly improved(P＜0.001).Conclusion Adipose derived MSC-Exo play a role in inhibiting adverse ventricular remodeling after MI by regulating the balance of autophagy and NLRP3 inflammasomes.

Objective To explore the value of non-contrast CT findings of acute ischemic stroke(AIS)for predicting early prognosis after mechanical thrombectomy.Methods Data of 161 AIS patients from clinical center 1 who underwent mechanical thrombectomy were retrospectively analyzed.The patients were divided into training set(n=113)and internal test set(n=48)at the ratio of 7∶3,while 79 AIS patients who underwent mechanical thrombectomy from clinical center 2 were retrospectively enrolled as external test set.According to the National Institutes of Health stroke scale(NIHSS)scores 7 days after thrombectomy,patients'prognosis were classified as good(＜15 points)or poor(≥15 points).Pre-treatment non-contrast CT images of patients were reviewed,and CT findings were comparatively analyzed.Independent predictors of patients'early prognosis after mechanical thrombectomy were obtained with sequential univariate and multivariate logistic regressions,and a predicting model was established and visualized as a nomogram.The receiver operating characteristic curve was drawn,and the distinction was assessed with the area under the curve(AUC),then calibration was assessed with Hosmer-Lemeshow goodness of fit test,and the net benefit was evaluated with decision curve analysis(DCA).Results Alberta stroke program early CT score(ASPECTS),hyperdense middle cerebral artery sign(HMCAS)and basal ganglia calcification were all independent predictors of early prognosis of AIS after mechanical thrombectomy(all P＜0.05).The predictive model was established combining the above 3 variables and then visualized as a nomogram to predict prognosis of AIS after mechanical thrombectomy,with AUC of 0.776 in internal test set(χ2=6.052,P=0.417)and 0.800 in external test set(χ2=2.269,P=0.811).DCA showed that the nomogram might provide clinical net benefit within certain threshold probability ranges.Conclusion ASPECTS,HMCAS and basal ganglia calcification were all independent predictors of early prognosis of AIS after mechanical thrombectomy.The nomogram originated from predicting model combining the three could be used to somewhat accurately predict poor early prognosis after mechanical thrombectomy.

Objective To investigate the value of iterative decomposition of water and fat with echo asymmetry and least-squares(IDEAL-IQ)sequence in evaluating the correlation between renal ectopic fat deposition and early diabetic kidney disease(DKD)in patients with diabetes mellitus(DM).Methods A total of 51 patients with T1DM or T2DM were enrolled in this study from the Endocrinology and Metabolism Department in Affiliated Jinhua Hospital,Zhejiang University School of Medicine during January 2022 to July 2023.All the patients were divided into two groups according to the results of urine albumin creatinine ratio(UACR):normal or slightly increased urinary micro albumin group(NAU,UACR<30 mg/g,n=27)and diabetic kidney disease group(DKD,UACR 30～300 mg/g,n=24).Meanwhile,55 healthy subjects in health examination were selected as control group(NC).Pearson correlation analysis was used to analyze the correlation between renal FF and other indicators.Logistic regression analysis was used to analyze the influencing factors of early DKD,and the diagnostic efficiency of renal FF for early DKD was analyzed by the ROC curve.Results Serum creatinine(Scr)and renal fat fraction(FF)value were higher in DKD group than in NC and NAU groups(P<0.05).Pearson correlation analysis showed that kidney FF were positively correlated with UACR and Hcy(P<0.05).Logistic regression analysis showed that after adjusting for confounding factors,renal FF was a contributing factor to early DKD.The ROC curve revealed that model 2 had the highest diagnostic efficiency,with AUC=0.801,sensitivity of 66.7%,specificity of 85.2%,accuracy of 80.0%,and a renal FF cut-off value was 2.46%.Conclusion IDEAL-IQ could non-invasively measure the renal fat content in DM patients,and the renal FF were significantly associated with DKD in early stage.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.