Stroke is one of the most common and serious neurological complications associated with extracorporeal membrane oxygenation （ECMO） therapy， and close monitoring， early recognition， and timely intervention can reduce the incidence rate of stroke and the mortality rate of patients. Transcranial Doppler （TCD） and transcranial color Doppler ultrasonography （TCCD） have emerged as the preferred modalities for monitoring cerebral blood flow in ECMO patients due to their bedside applicability， ability to provide real-time dynamic assessments， and noninvasive safety. This article summarizes the spectral characteristics of cerebral blood flow in patients undergoing various ECMO modalities and elaborates on the latest research advances and clinical significance of TCD/TCCD in predicting stroke events， monitoring cerebral microembolic signals， reflecting the change in intracranial pressure， confirming brain death， and providing prognostic evaluation.
Stroke

OBJECTIVE: To explore the rules of acupoint selection and compatibility of acupuncture and moxibustion in treatment of chronic cough using data mining. METHODS: The ancient and modern medical record cloud platform, and the databases, i.e. CNKI, Wanfang, VIP, EMbase, Web of Science and PubMed, were searched to screen the ancient and modern literature on acupuncture and moxibustion treatment of chronic cough. The prescription database was established for acupuncture and moxibustion treatment of chronic cough, and the analysis conducted on the frequency and use percentage in the aspects of intervention measures, acupoint selection, acupoint distribution, meridian tropism, special points and acupoint combination, as well as the association rules and clustering rules of acupoint selection. The subgroup analysis was performed in accordance with the etiology of chronic cough and intervention measures. RESULTS: A total of 106 articles were included and 158 prescriptions were extracted. The intervention measures were acupuncture, moxibustion, herbal medication and the combination of several measures. The high-frequency acupoints included Feishu (BL13), Zusanli (ST36), Dazhui (GV14), Pishu (BL20), Danzhong (CV17), Shenshu (BL23), Lieque (LU7), Dingchuan (EX-B1), Tiantu (CV22), and Fenglong (ST40). These acupoints are mainly distributed on the back, lumbar region, chest and abdomen. The involved meridians were bladder meridian of foot-taiyang, conception vessel, and lung meridian of hand-taiyin. The special points covered back-shu points, crossing points and five-shu point. Regarding the compatibility of acupoints, the combination of upper and lower points, and the combination of front and back points were predominant in treatment. The analysis of association rules found that the support of Feishu (BL13)→Zusanli (ST36) was the highest; the cluster analysis obtained 8 clusters of acupoints. The acupoint compatibility and overall rules were similar when cough variant asthma (CVA) or the mixed reasons were involved, and the local treatment approach was adopted if the etiology of disease was related to upper airway cough syndrome (UACS) and gastroesophageal reflux cough (GERC). The acupoint selection was similar among different intervention measures. When two kinds of measures were combined in treatment, Feishu (BL13), Pishu (BL20) and Zusanli (ST36) were the most common. CONCLUSION In treatment with acupuncture and moxibustion for chronic cough, the acupoints are selected on the affected local area, depending on syndrome differentiation, and focusing on back-shu points. The main acupoints are Feishu (BL13), Zusanli (ST36), Dazhui (GV14), Pishu (BL20), Danzhong (CV17) and Shenshu (BL23). The combined therapy is dominant with acupuncture, moxibustion and herbal medicine involved.
Acupuncture Points ; Moxibustion/history* ; Humans ; Cough/history* ; Acupuncture Therapy/history* ; Chronic Disease/therapy* ; Data Mining ; History, Ancient ; Meridians ; Chronic Cough

Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

ObjectiveTo investigate the association between cumulative atherogenic index of plasma （cumAIP） and the risk of new-onset nonalcoholic fatty liver disease （NAFLD） in young and middle-aged individuals. MethodsA prospective cohort study was conducted among the young and middle-aged individuals （aged 18 to <60 years） in the Kailuan study cohort who underwent physical examination in Kailuan General Hospital and its 10 affiliated hospitals in June 2006 to October 2010， and after screening based on the inclusion and exclusion criteria， 33 987 individuals were included in the observation cohort. The individuals were divided into Q1， Q2， Q3， and Q4 groups based on the quantiles of cumAIP. The Kaplan-Meier method was used to calculate the cumulative incidence rate of new-onset NAFLD in the four groups， while the log-rank test was used for comparison between groups. A multivariate Cox regression analysis was used to obtain the hazard ratio （HR） and 95% confidence interval （CI） of the risk of new-onset NAFLD in the four groups. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups； the chi-square test was used for comparison of categorical variables between groups. ResultsThe mean follow-up was 10.89±2.54 years， and there were 6 011 cases of new-onset NAFLD， including 995 cases in the Q1 group， 1 366 in the Q2 group， 1661 in the Q3 group， and 1 989 in the Q4 group， with an incidence density of 11.37， 16.02， 19.97， and 24.91 per thousand person-years. The log-rank test showed that there was a significant difference in cumulative incidence rate between the four groups （P<0.001）. With the presence or absence of NAFLD as the dependent variable and the quantiles of different exposure levels to cumAIP as the independent variable， the multivariate Cox regression model analysis showed that compared with the Q1 group， the Q2， Q3， and Q4 groups had an HR of 1.30 （95%CI： 1.20 — 1.41）， 1.52 （95%CI： 1.41 — 1.65）， and 1.79 （95%CI： 1.64 — 1.95）， respectively， for new-onset NAFLD， with a P_trend value of <0.001. With the presence or absence of new-onset NAFLD as the dependent variable and the cumulative exposure to AIP for 0， 2， 4， and 6 years as the independent variable， the Cox regression analysis showed that compared with cumulative exposure to AIP for 0 years， cumulative exposure to AIP for 2， 4， and 6 years had an HR of 1.24 （95%CI： 1.15 — 1.35）， 1.51 （95%CI： 1.40 — 1.64）， and 1.70 （95%CI： 1.56 — 1.84）， respectively， with a P_trend value of <0.001. A sensitivity analysis was performed after exclusion of the individuals with new-onset NAFLD within 2 years， the individuals who experienced atherosclerotic cardiovascular disease events during follow-up， and the individuals taking antihypertensive， hypoglycemic， and lipid-lowering drugs， and the results were similar to those of the main analysis. Considering the competitive relationship between all-cause death and outcome events， a competing risk analysis of death was performed， which showed that the results of risk analysis were similar to those of the main analysis. ConclusionA high level of cumAIP exposure can increase the risk of new-onset NAFLD in young and middle-aged individuals.

Objective: To summarize the treatment methods and efficacy of a patient with pure red cell aplasia (PRCA) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and to accumulate relevant case data. Methods: The clinical treatment and laboratory test data of a patient with PRCA after allo-HSCT in our hospital were retrospectively collected. The therapeutic strategy, monitoring parameters, and treatment outcomes were summarized. Results: Upon suspicion of post-transplant PRCA, the patient was promptly treated with intravenous injection of human immunoglobulin and three sessions of plasma exchange. The titer of blood group antibodies in the patient decreased, and the hemolytic symptoms were relieved. Over one year post-transplantation, the patient exhibited a sustained impairment of erythropoiesis, necessitating continued red blood cell transfusions. After treatment with intravenous daratumumab (400 mg twice weekly for 4 weeks), the pateint's hemoglobin (Hb) and reticulocyte (Ret) levels normalized rapidly, the ABO blood type converted from the recipient to the donor type, and the titer of IgM blood group antibodies returned to normal. The patient was successfully weaned off red blood cell transfusions, indicating the clinical efficacy of the treatment. Conclusion: Daratumumab shows effectiveness in the treatment of refractory PRCA after allo-HSCT in the case. It is essential to monitor Hb, Ret and the titer of blood group antibodies during treatment. Nevertheless, the interference of daratumumab with the titer of blood group antibodies should be considered.

ObjectiveTo identify the prototypical components and metabolites absorbed into blood and cerebrospinal fluid of Schisandrae Chinensis Fructus（SCF） based on sequential metabolism combined with liquid chromatography-mass spectrometry. MethodBlood and cerebrospinal fluid samples of integrated metabolism， intestinal metabolism and hepatic metabolism were collected from male SD rats after gavage and in situ intestinal perfusion administration， and ultra-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry（UPLC Q-Exactive Orbitrap MS） was used to analyze and compare the differences in the spectra of SCF extract， blank plasma， administered plasma， blank cerebrospinal fluid and administered cerebrospinal fluid with ACQUITY UPLC BEH Shield RP18 column（2.1 mm×100 mm， 1.7 µm）， the mobile phase was acetonitrile（A）-0.1% formic acid aqueous solution（B） for gradient elution（0-7 min， 95%B； 7-12 min， 95%-35%B； 12-17 min， 35%-15%B； 17-20 min， 15%-12%B； 20-22 min， 12%-5%B； 22-23 min， 5%B； 23-25 min， 5%-95%B； 25-28 min， 95%B）. And heated electrospray ionization（HESI） was used with positive and negative ion modes， the scanning range was m/z 100-1 500. The prototypical constituents and their metabolites absorbed into blood and cerebrospinal fluid of SCF were identified according to the retention time， characteristic fragments， molecular formulae and the information of reference substances. ResultA total of 42 chemical components were identified in the extract of SCF， including lignans， flavonoids， amino acids， tannins， and others， of which lignans were the main ones. A total of 27 prototypical components and 14 metabolites were identified in plasma samples from different sites. A total of 15 prototypical components and 9 metabolites were identified in cerebrospinal fluid. The main metabolic reactions involved in the formation of metabolites were mainly demethylation， methylation， demethoxylation and hydroxylation. ConclusionThrough the systematic identification of the prototypical components and metabolites of SCF in rats， it provides data support for further better exploring the material basis of SCF in the treatment of central nervous system diseases.

Objective:To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021.Methods:Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison.Results:Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions:Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Objective To explore the mechanism of plumbagin for protecting against sepsis-induced myocardial injury in mice.Methods Network pharmacology analysis was used to obtain the key targets of plumbagin and diseases,which were subjected to GO and KEGG analysis,and the binding energy was verified using molecular docking.In a mouse model of cecal ligation and puncture(CLP),the protective effect of plumbagin treatment prior to CLP against sepsis-induced myocardial injury was evaluated by examination of myocardial function and pathology using echocardiography and HE staining.Serum levels of CK-MB,LDH,MDA,IL-1β and IL-18 and myocardial ROS level in the mice were detected,and Western blotting was used to determine the protein expression levels of STAT3,GSDMD,caspase-11,JAK2,P-STAT3,P-JAK2,GSDMD-N and HMGB1 in the myocardial tissues.Results Five core targets were screened from the 10 intersecting genes.Molecular docking showed strong binding affinity of plumbagin to STAT3,p-STAT3,and JAK2.Compared with the sham-operated mice,the mouse models of CLP-induced sepsis had significantly decreased CO,LVEF,LVFS and SV and increased serum levels of CK-MB,LDH,MDA and myocardial inflammatory factors and ROS.HE staining and Western blotting showed obvious myocardial injury in the septic mice with increased expressions of JAK2/STAT3 signaling pathway and pyroptosis-related proteins(P<0.05).Pretreatment with plumbagin significantly improved cardiac functions of CLP mice,lowered serum levels of CK-MB,LDH,MDA,inflammatory factors and myocardial ROS,and decreased the expression levels of JAK2/STAT3 signaling pathway and pyroptosis-related proteins.Conclusion Plumbagin pretreatment alleviates myocardial injury in septic mice possibly by inhibiting the STAT3 signaling pathway to reduce cardiomyocyte pyroptosis.

Objective To explore the mechanism of plumbagin for protecting against sepsis-induced myocardial injury in mice.Methods Network pharmacology analysis was used to obtain the key targets of plumbagin and diseases,which were subjected to GO and KEGG analysis,and the binding energy was verified using molecular docking.In a mouse model of cecal ligation and puncture(CLP),the protective effect of plumbagin treatment prior to CLP against sepsis-induced myocardial injury was evaluated by examination of myocardial function and pathology using echocardiography and HE staining.Serum levels of CK-MB,LDH,MDA,IL-1β and IL-18 and myocardial ROS level in the mice were detected,and Western blotting was used to determine the protein expression levels of STAT3,GSDMD,caspase-11,JAK2,P-STAT3,P-JAK2,GSDMD-N and HMGB1 in the myocardial tissues.Results Five core targets were screened from the 10 intersecting genes.Molecular docking showed strong binding affinity of plumbagin to STAT3,p-STAT3,and JAK2.Compared with the sham-operated mice,the mouse models of CLP-induced sepsis had significantly decreased CO,LVEF,LVFS and SV and increased serum levels of CK-MB,LDH,MDA and myocardial inflammatory factors and ROS.HE staining and Western blotting showed obvious myocardial injury in the septic mice with increased expressions of JAK2/STAT3 signaling pathway and pyroptosis-related proteins(P<0.05).Pretreatment with plumbagin significantly improved cardiac functions of CLP mice,lowered serum levels of CK-MB,LDH,MDA,inflammatory factors and myocardial ROS,and decreased the expression levels of JAK2/STAT3 signaling pathway and pyroptosis-related proteins.Conclusion Plumbagin pretreatment alleviates myocardial injury in septic mice possibly by inhibiting the STAT3 signaling pathway to reduce cardiomyocyte pyroptosis.