BACKGROUND:Our previous study found that Modified Erxian Pill could alleviate inflammation in collagen-induced arthritis rats,but its mechanism needs to be further verified. OBJECTIVE:To analyze the components absorbed in the blood of Modified Erxian Pill,and observe the effect of the drug-containing serum of Modified Erxian Pill on pyroptosis of J774A.1 macrophages. METHODS:(1)Analysis of components absorbed in the blood of Modified Erxian Pill:Ultra-high performance liquid chromatography-high resolution mass spectrometry was used to detect and identify Modified Erxian Pill and its components absorbed in the blood.(2)Effect of the drug-containing serum of Modified Erxian Pill on pyroptosis of J774A.1 macrophages:Molecular docking technology was used to initially verify the sesquiterpenoids and NLRP3 in components absorbed in the blood of Modified Erxian Pill.J774A.1 macrophages were randomly divided into blank control group,lipopolysaccharide+adenosine triphosphate group,and lipopolysaccharide+adenosine triphosphate+Modified Erxian Pill with low(2.5%),medium(5%),and high(10%)dose groups.The release of lactate dehydrogenase in the cell supernatant of each group was detected according to the kit instructions.The levels of interleukin-1β and interleukin-18 in cell supernatant were detected in each group by ELISA.The cell membrane damage was detected by Hoechst/PI staining.The expression levels of NLRP3,Caspase-1,GSDMD,and GSDMD-N protein in the cells of each group were detected by western blot assay. RESULTS AND CONCLUSION:(1)A total of 32 active components of Modified Erxian Pill were identified,and 21 components entered the blood.The main components into blood included a variety of sesquiterpenoids.(2)Molecular docking results showed that 3-O-Acetyl-13-deoxyphomenone,Incensol oxide,Atractylenolide III,Rupestonic acid,and 3,7-Dihydroxy-9,11-eremophiladien-8-one had good binding activity with NLRP3.(3)Compared with the blank control group,lactate dehydrogenase activity and the expression levels of interleukin-1β and interleukin-18 were significantly increased in cell supernatant of lipopolysaccharide+adenosine triphosphate group(P<0.001).Hoechst/PI staining showed that the number of PI-positive cells was significantly increased.After the intervention of lipopolysaccharide+adenosine triphosphate+Modified Erxian Pill group,all of them showed different degrees of reduction.(4)Compared with the blank control group,NLRP3,Caspase-1,GSDMD,and GSDMD-N protein expression levels were significantly increased in the lipopolysaccharide+adenosine triphosphate group(P<0.05).Compared with lipopolysaccharide+adenosine triphosphate group,the protein expressions of NLRP3,Caspase-1,GSDMD,and GSDMD-N were significantly decreased in the lipopolysaccharide+adenosine triphosphate+Modified Erxian Pill group(P<0.05),and had a certain dose dependence.These findings verify that the drug-containing serum of Modified Erxian Pill may inhibit the pyroptosis of J774A.1 macrophages by regulating the NLRP3/Caspase-1/GSDMD pathway.

OBJECTIVE To prepare polyethylene glycol （PEG）-modified flower lactose （FL） loaded Curcumin （Cur） solid lipid nanoparticle （SLN） inhalable micropowder （referred to as “PEG-Cur-FL”）. METHODS PEG-Cur-FL was prepared by the solvent emulsification diffusion low-temperature solidification method， and its encapsulation efficiency， drug loading capacity， powder properties， aerodynamic particle size， in vitro deposition properties， and in vitro release characteristics were characterized. The mice were divided into Cur-SLN-FL （unmodified with PEG） group and PEG-Cur-FL group， with 55 mice in each group. Both groups of mice were given a single inhalation of 5 mg/kg （calculated as Cur） of the corresponding drug micropowder through an air tube. At 0.25， 0.5， 1， 2， 4， 6， 8， 12， 24， 48 and 72 hours after administration， eyeballs were removed to collect blood and tracheal， lung， liver and kidney tissues were separated. The mass concentration of Cur in mouse plasma and various tissue samples was measured， and the tissue distribution and retention of the drug were analyzed. RESULTS The encapsulation efficiency and drug loading capacity of PEG-Cur-FL were （86.2±1.8）% and （4.2±0.2）%， respectively； the bulk density and tap density were （0.24±0.01） g/cm3 and （0.30±0.01） g/cm3， respectively； the aerodynamic particle size was （2.74±0.64） μm； the in vitro effective site deposition rate （secondary drug deposition rate） was （45.07±2.79）%. Compared with Cur raw materials， Cur-SLN- FL and PEG-Cur-FL had sustained release effects under both leakage and non-leakage conditions， and PEG-Cur-FL had a smoother sustained release in artificial lung fluid， with release characteristics consistent with the Weibull model. The results of in vivo distribution showed that the drug concentration in the lung tissue of PEG-Cur-FL group was significantly lower than that of Cur- SLN-FL group during the same period after 1 hour of administration， while the drug concentration in the lung tissue at 4 to 48 hours was significantly higher than that of Cur-SLN-FL group during the same period （P＜0.05）； the plasma drug concentrations of the PEG-Cur-FL group at all time points from 0.25 to 12 hours were significantly lower than those of the Cur-SLN-FL group during the same period （P＜0.05）， and the drug concentrations in liver and kidney tissues were also lower than those of the Cur-SLN-FL group during the same period （P＜0.05）. CONCLUSIONS PEG-Cur-FL is prepared successfully； the inhalable micropowder has good inhalability and release performance； after administration through the trachea， the effective concentration of Cur in lung tissue can be increased， while reducing its plasma drug concentration and drug distribution concentration in non-target organs.

Objective:To investigate the safety and efficacy of balloon pulmonary angioplasty (BPA) for residual pulmonary hypertension (PH) of chronic thromboembolic pulmonary hypertension(CTEPH) after pulmonary endarterectomy (PEA).Methods:Patients diagnosed as PH after PEA in China-Japan Friendship Hospital from Oct 2016 to Jun 2022 were included. The indication for BPA was decided on the basis of a consensus of the multi-disciplinary team for all patients with CTEPH. Before treatment, the patient′s exercise tolerance and pulmonary artery flow parameters were evaluated. A comparative analysis of various parameters before BPA treatment and at the last BPA was conducted. 6-min walk distance (6MWD) was analyzed using the paired Wilcoxon test; N-terminal pro-brain natriuretic peptide (NT-proBNP), mixed venous oxygen saturation, mean pulmonary arterial pressure (mPAP), cardiac index (CI) and pulmonary vascular resistance (PVR) were compared using the paired-samples t-test. WHO functional class was compared using McNemar′s test. Results:Twenty patients with a total of 130 vessels underwent 46 sessions of BPA treatment. The postoperative 6-minute walk distance (6MWD) [447 (415, 485) m] showed a significant improvement compared to the preoperative baseline [389 (335, 470) m] ( Z=6.52, P<0.05), Postoperative mixed venous oxygen saturation (72.0%±1.9%) showed a significant improvement compared to the preoperative levels (64.0%±2.7%) ( t=2.14, P<0.05).Postoperatively, plasma NT-proBNP [(351.9±129.9) pg/ml], mPAP [(24.2±1.9) mmHg], and PVR [(3.0±1.4) WU] significantly decreased compared to preoperative levels [(982.5±426.2) pg/ml, (33±2.1) mmHg, (8.0±1.6) WU)] ( t=3.38, 1.22, 2.10, P<0.05 for all). Postoperatively, there was a significant improvement in WHO functional class (Ⅰ，Ⅱ，Ⅲ，Ⅳ: 14, 4, 2, 0 cases) compared to preoperative status (Ⅰ，Ⅱ，Ⅲ，Ⅳ: 0, 13, 5, 2 cases) ( χ2=20.17, P<0.05). Four cases of pulmonary artery dissection and one episode of hemoptysis occurred postoperatively, with no other complications reported. Conclusions:BPA can significantly improve exercise tolerance and hemodynamic parameters for residual PH after PEA. BPA is a relatively safe and effective treatment for residual PH after PEA.

The incidence of intrahepatic cholangiocarcinoma (ICC) continues to rise, and there are no effective drugs to treat it. The immune microenvironment plays an important role in the development of ICC and is currently a research hotspot. Icaritin (ICA) is an innovative traditional Chinese medicine for the treatment of advanced hepatocellular carcinoma. It is considered to have potential immunoregulatory and anti-tumor effects, which is potentially consistent with the understanding of "Fuzheng" in the treatment of tumor in traditional Chinese medicine. However, whether ICA can be used to treat ICC has not been reported. Therefore, in this study, sgp19/kRas, an in situ ICC mouse model with intact immune system, was selected to evaluate the efficacy of ICA in the treatment of ICC in vivo for the first time, and the effects of ICA on the tumor immune microenvironment of ICC mice were analyzed by flow cytometry. This experiment was approved by the Experimental Animal Ethics Committee of Capital Medical University (approval number: AEEI-2023-138). In this study, sgp19/kRas ICC mouse model was treated with oral gavage of 100 mg·kg^-1 ICA. We found that ICA significantly inhibited tumor growth and tumor cell proliferation in the sgp19/kRas ICC mouse model after 3 weeks of treatment. Flow cytometry analysis indicated that ICA treatment markedly reduced the proportion of M2 macrophages and increased the number of CD3⁺CD4⁺ T cells. In vitro experiments demonstrated that ICA promoted macrophage polarization towards the M1 phenotype while inhibiting polarization towards the M2 phenotype. Furthermore, transcriptomic analysis suggested that ICA enhanced Toll-like receptor 9 (TLR9) expression, influencing macrophage nitric oxide metabolism synthesis pathways and receptor-related activities, thereby regulating macrophage polarization. In summary, this study demonstrates that ICA treatment significantly delays tumor progression in sgp19/kRas ICC mouse models. Mechanistically, ICA may achieve its anti-ICC effects by upregulating TLR9 receptor expression levels, promoting macrophage polarization towards the M1 phenotype, and altering the tumor immune microenvironment.

Objective:To construct a nomogram model for predicting the 28-day mortality of patients with septic shock in the emergency medicine department and to validate the predictive efficacy.Methods:Based on the database of the emergency medicine department of Chu Hsien-I Memorial Hospital of Tianjin Medical University, Tianjin Medical University General Hospital and the Second Hospital of Tianjin Medical University, the data of 913 patients with septic shock admitted to the emergency medicine department from January 2017 to October 2020 were collected, including baseline demographic information and clinical characteristics, laboratory indices, and the main endpoints (28-day mortality). The patients were divided into a training set and a validation set based on simple random sampling. All significant variables from the one-way binary Logistic regression analysis of the training set were included in the multivariate Logistic regression analysis to analyze the risk factors for 28-day mortality in patients with septic shock and to construct a column-line graphical model. The predictive efficacy of the nomogram model was assessed using calibration curves and receiver operator characteristic curve (ROC curve).Results:A total of 860 patients with septic shock meeting the criteria were finally enrolled, including 472 in the training set and 388 in the validation set. The 28-day mortalities were 52.5% (248/472) and 54.1% (210/388) for the training and validation sets, respectively. In the training set, age, respiratory rate (RR), the levels of C-reactive protein (CRP), D-dimer, white blood cell count (WBC), neutrophil count (NEU), neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), mean platelet volume (MPV), and platelet count (PLT) in the death group were significantly higher than those in the survival group, and the levels of base remaining (BE), lymphocyte count (LYM), hemoglobin (Hb) and the proportion of chronic obstructive pulmonary diseases (COPD) were significantly lower than those in the survival group (all P < 0.05). Multifactorial Logistic regression analysis showed that NLR [odds ratio ( OR) = 0.023 0, 95% confidence interval (95% CI) was -0.204 4 to 0.113 0], MPV ( OR = 0.179 8, 95% CI was -0.877 6 to 0.172 7), Hb ( OR = 0.007 8, 95% CI was 0.010 3 to 0.040 8), procalcitonin (PCT; OR = 1.957 0, 95% CI was 1.243 0 to 3.081 0), and D-dimer ( OR = 0.000 1, 95% CI was -0.000 4 to 0.000 1) were independent predictors of 28-day mortality in patients with septic shock in the emergency department (all P < 0.05). A column-line graph model was established based on the above variables, and the ROC curves showed that the area under the ROC curve (AUC) of the nomogram model in the training set and validation set for predicting the 28-day mortality of patients with septic shock was 0.907 (95% CI was 0.864 to 0.940) and 0.822 (95% CI was 0.781 to 0.863), respectively. The calibration curves showed good agreement between the predicted and observed results for both the training and validation sets. Conclusion:The nomogram model constructed based on NLR, MPV, Hb, PCT and D-dimer has significant clinical value in predicting the 28-day mortality of patients with septic shock in the emergency medicine department.

With the in-depth study of molecular biology,non-small cell lung cancer(NSCLC)has opened the era of precision medicine based on mutation-based molecular targeting therapy.Epidermal growth factor receptor(EGFR)driver mutations are closely related to the progression of NSCLC,and EGFR-tyrosine kinase inhibitors(TKIs)developed based on this have achieved significant therapeutic effects,but acquired drug resistance is still one of the major factors limiting their long-term use.As resistance mechanisms are further investigated,in addition to secondary EGFR mutation,MET amplification,HER2 amplification,histologic transformation,etc.,receptor tyrosine kinase(RTK)fusion mutation have been shown to be a targetable mechanism of acquired resistance.Among the acquired RTK fusion mutations,rearranged during transfection(RET)fusion mutations are the accessible targets of our concern.As the RET molecule continues to be explored,drugs targeting RET fusions have been approved and marketed.There are different clinical strategies to deal with acquired RET fusion mutation mediating resistance to EGFR-TKIs treatment.In this review,the structure and function of RET,its relationship with EGFR-TKIs resistance,and treatment strategies are reviewed to further improve patient survival outcomes.

Human brain banks use a standardized protocol to collect,process and store post-mortem human brains and related tissues,along with relevant clinical information,and to provide the tissue samples and data as a resource to foster neuroscience research according to a standardized operating protocols(SOP).Human brain bank serves as the foundation for neuroscience research and the diagnosis of neurological disorders,highlighting the crucial rule of ensuring the consistency of standardized quality for brain tissue samples.The first version of SOP in 2017 was published by the China Human Brain Bank Consortium.As members increases from different regions in China,a revised SOP was drafted by experts from the China Human Brain Bank Consortium to meet the growing demands for neuroscience research.The revised SOP places a strong emphasis on ethical standards,incorporates neuropathological evaluation of brain regions,and provides clarity on spinal cord sampling and pathological assessment.Notable enhancements in this updated version of the SOP include reinforced ethical guidelines,inclusion of matching controls in recruitment,and expansion of brain regions to be sampled for neuropathological evaluation.

Aim To explore the effect of quercetin(Que)on ferroptosis and the potential mechanisms in an Erastin-induced ferroptosis model in chondrocytes.Methods A model of Erastin-induced ferroptosis was established in C28/I2 chondrocytes.Cells were treated with different concentrations of Que.Cell viability and cytotoxicity were assessed by MTT and LDH assays.The expression levels of Prdx6 and ferroptosis-related proteins ACSL4 and GPX4 in chondrocytes were deter-mined by Western blot.Lipid ROS production in chon-drocytes was measured by flow cytometry,while the changes in mitochondrial membrane potential were de-tected by RH123 staining.Prdx6 mRNA expression in chondrocytes was quantified by RT-qPCR.The chan-ges in the expression of the ferroptosis-related proteins ACSL4 and GPX4 were detected by immunofluores-cence staining.Results Compared to the Erastin-in-duced ferroptosis model group,Que significantly im-proved the viability of C28/I2 chondrocytes and re-duced cell cytotoxicity.It decreased the expression of the ferroptosis-related protein ACSL4 and increased the expression of GPX4.Que also inhibited the production of lipid ROS in chondrocytes and strengthened their mitochondrial membrane potential.In addition,the ex-pression of Prdx6 was significantly reduced in the Eras-tin group compared to the control group,while Que treatment upregulated the expression of Prdx6.Mean-while,the inhibitory effect of Que on chondrocyte fer-roptosis was reduced by the use of MJ33,an inhibitor of Prdx6.Conclusion Que can inhibit Erastin-induced ferroptosis of C28/I2 chondrocytes,possibly by upregu-lating Prdx6,and thus play a protective role in chon-drocytes.

Objective To explore the association between violent behaviors and emotions in individuals with mental disorders,to evaluate the application value of facial expression analysis technology in violence risk assessment of individuals with mental disorders in supervised settings,and to provide a reference for violence risk assessment.Methods Thirty-nine male individuals with mental disorders in supervised settings were selected,the participant risk of violence,cognitive function,psychiatric symptoms and se-verity were assessed using the Modified Overt Aggression Scale (MOAS),the Historical,Clinical,Risk Management-Chinese version(HCR-CV),the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS).An emotional arousal was performed on the participants and the intensity of their emotions and facial expression action units was recorded before,during and after the arousal.One-way analysis of variance (ANOVA) was used to compare the differences in the intensity of emotions and facial expression action units before,during and after the arousal.Pearson correlation analysis was used to calculate the correlations between the intensity of the seven basic emo-tional facial expressions and the scores of the assessment scales.Results The intensity difference of sadness,surprise and fear in different time periods was statistically significant (P<0.05).The intensity of the left medial eyebrow lift action unit was found significantly different before and after the emo-tional arousal (P<0.05).The intensity of anger was positively correlated with the Modified Overt Ag-gression Scale score throughout the experiment (P<0.05).Conclusion Eye action units such as eye-brow lifting,eyelid tightening and upper eyelid lifting can be used as effective action units to identify sadness,anger and other negative emotions associated with violent behaviors.Facial expression analysis technology can be used as an auxiliary tool to assess the potential risk of violence in individuals with mental disorders in supervised settings.

With the increasing proportion of human papilloma virus(HPV)infection in the pathogenic factors of oro-pharyngeal cancer,a series of changes have occurred in the surgical treatment.While the treatment mode has been im-proved,there are still many problems,including the inconsistency between diagnosis and treatment modes,the lack of popularization of reconstruction technology,the imperfect post-treatment rehabilitation system,and the lack of effective preventive measures.Especially in terms of treatment mode for early oropharyngeal cancer,there is no unified conclu-sion whether it is surgery alone or radiotherapy alone,and whether robotic minimally invasive surgery has better func-tional protection than radiotherapy.For advanced oropharyngeal cancer,there is greater controversy over the treatment mode.It is still unclear whether to adopt a non-surgical treatment mode of synchronous chemoradiotherapy or induction chemotherapy combined with synchronous chemoradiotherapy,or a treatment mode of surgery combined with postopera-tive chemoradiotherapy.In order to standardize the surgical treatment of oropharyngeal cancer in China and clarify the indications for surgical treatment of oropharyngeal cancer,this expert consensus,based on the characteristics and treat-ment status of oropharyngeal cancer in China and combined with the international latest theories and practices,forms consensus opinions in multiple aspects of preoperative evaluation,surgical indication determination,primary tumor re-section,neck lymph node dissection,postoperative defect repair,postoperative complication management prognosis and follow-up of oropharyngeal cancer patients.The key points include:① Before the treatment of oropharyngeal cancer,the expression of P16 protein should be detected to clarify HPV status;② Perform enhanced magnetic resonance imaging of the maxillofacial region before surgery to evaluate the invasion of oropharyngeal cancer and guide precise surgical resec-tion of oropharyngeal cancer.Evaluating mouth opening and airway status is crucial for surgical approach decisions and postoperative risk prediction;③ For oropharyngeal cancer patients who have to undergo major surgery and cannot eat for one to two months,it is recommended to undergo percutaneous endoscopic gastrostomy before surgery to effectively improve their nutritional intake during treatment;④ Early-stage oropharyngeal cancer patients may opt for either sur-gery alone or radiation therapy alone.For intermediate and advanced stages,HPV-related oropharyngeal cancer general-ly prioritizes radiation therapy,with concurrent chemotherapy considered based on tumor staging.Surgical treatment is recommended as the first choice for HPV unrelated oropharyngeal squamous cell carcinoma(including primary and re-current)and recurrent HPV related oropharyngeal squamous cell carcinoma after radiotherapy and chemotherapy;⑤ For primary exogenous T1-2 oropharyngeal cancer,direct surgery through the oral approach or da Vinci robotic sur-gery is preferred.For T3-4 patients with advanced oropharyngeal cancer,it is recommended to use temporary mandibu-lectomy approach and lateral pharyngotomy approach for surgery as appropriate;⑥ For cT1-2N0 oropharyngeal cancer patients with tumor invasion depth＞3 mm and cT3-4N0 HPV unrelated oropharyngeal cancer patients,selective neck dissection of levels ⅠB to Ⅳ is recommended.For cN+HPV unrelated oropharyngeal cancer patients,therapeutic neck dissection in regions Ⅰ-Ⅴ is advised;⑦ If PET-CT scan at 12 or more weeks after completion of radiation shows intense FDG uptake in any node,or imaging suggests continuous enlargement of lymph nodes,the patient should undergo neck dissection;⑧ For patients with suspected extracapsular invasion preoperatively,lymph node dissection should include removal of surrounding muscle and adipose connective tissue;⑨ The reconstruction of oropharyngeal cancer defects should follow the principle of reconstruction steps,with priority given to adjacent flaps,followed by distal pedicled flaps,and finally free flaps.The anterolateral thigh flap with abundant tissue can be used as the preferred flap for large-scale postoperative defects.