Acute pancreatitis (AP) is a life-threatening gastrointestinal disorder for which no effective pharmacological treatments are currently available. One of the pharmacological targets that merits further research is the neurokinin 1 receptor (NK1R), which is found on pancreatic acinar cells and responds to the neuropeptide substance P (SP) that participates in AP. Although a few studies have stated the involvement of SP/NK1R in neurogenic inflammation in AP development, the regulatory mechanism remains unclear. In this study, we found that following activation of NK1R by SP, β-arrestin1, a scaffold protein of NK1R, down-regulated transcription of Adss, Adsl, and Ampd in the purine nucleotide cycle, thereby inhibiting mitochondrial function through fumarate depletion. Interestingly, we identified magnolol as a new and natural NK1R inhibitor with a non-nitrogenous biphenyl core structure. It exhibited a beneficial effect on AP by restoring purine nucleotide cycle metabolic enzymes and fumarate levels. Our study not only provides new therapeutic strategies, leading compounds, and drug translation possibilities for AP, but also provides important clues for the study of downstream mechanisms driven by SP in other diseases.

Lung cancer is the most common malignant tumor worldwide, ranking first in both incidence and mortality rates. According to the latest statistics from the International Agency for Research on Cancer (IARC), approximately 2.5 million new cases and around 1.8 million deaths from lung cancer occurred in 2022, placing a tremendous burden on global healthcare systems. The high mortality rate of lung cancer is closely linked to its subtle early symptoms, which often lead to diagnosis at advanced stages. This not only complicates treatment but also results in substantial economic losses. Current treatment options for lung cancer include surgery, radiotherapy, chemotherapy, targeted drug therapy, and immunotherapy. Among these, immunotherapy has emerged as the most groundbreaking advancement in recent years, owing to its unique antitumor mechanisms and impressive clinical benefits. Unlike traditional therapies such as radiotherapy and chemotherapy, immunotherapy activates or enhances the patient’s immune system to recognize and eliminate tumor cells. It offers advantages such as more durable therapeutic effects and relatively fewer toxic side effects. The main approaches to lung cancer immunotherapy include immune checkpoint inhibitors, tumor-specific antigen-targeted therapies, adoptive cell therapies, cancer vaccines, and oncolytic virus therapies. Among these, immune checkpoint inhibitors and tumor-specific antigen-targeted therapies have received approval from the U.S. Food and Drug Administration (FDA) for clinical use in lung cancer, significantly improving outcomes for patients with advanced non-small cell lung cancer. Although other immunotherapy strategies are still in clinical trials, they show great potential in improving treatment precision and efficacy. This article systematically reviews the latest research progress in lung cancer immunotherapy, including the development of novel immune checkpoint molecules, optimization of treatment strategies, identification of predictive biomarkers, and findings from recent clinical trials. It also discusses the current challenges in the field and outlines future directions, such as the development of next-generation immunotherapeutic agents, exploration of more effective combination regimens, and the establishment of precise efficacy prediction systems. The aim is to provide a valuable reference for the continued advancement of lung cancer immunotherapy.

Objective To develop and validate a predictive model for autologous arteriovenous fistula(AVF)maturation in hemodialysis patients using conventional ultrasonography and three-dimensional speckle tracking imaging.Methods This case-control study enrolled 200 AVF patients from Chongqing Hospital of Traditional Chinese Medicine from July 2021 to June 2024.Clinical data,vascular ultrasound,and cardiac ultrasound parameters were systematically collected.After applying predefined inclusion criteria,186 patients were stratified into 2 cohorts based on arteriovenous fistula(AVF)maturation status:the spontaneous maturation group(n=111)and the assisted maturation requirement group(n=75).Comparative analysis between the 2 cohorts was conducted using univariate and multivariate logistic regression for variable selection,leading to the construction of a predictive model(model1)for spontaneous AVF maturation.A nomogram was subsequently developed based on model1.Internal validation was performed through 1 000 bootstrap resamples with calibration curve analysis.Model discrimination was quantified by the area under the receiver operating characteristic curve(AUC),while clinical utility was assessed via decision curve analysis(DCA).After excluding 104 patients lacking three-dimensional speckle tracking echocardiography data,the remaining 82 subjects were included in novel predictive model development.Three strain parameters,two-dimensional global longitudinal strain(2DGLS),three-dimensional global longitudinal strain(3DGLS),and three-dimensional left ventricular ejection fraction(3DEF),were independently incorporated into multivariable logistic regression analyses to establish three distinct models(designated as model2,model3 and model4 respectively).Model comparisons employed AUC,net reclassification improvement(NRI),and integrated discrimination improvement(IDI).Results Independent predictors for model1 included:2DEF(OR=1.133,95%CI:1.058～1.213),mid-cephalic vein depth(OR=1.453,95%CI:1.068～1.978),distal cephalic vein diameter(OR=2.141,95%CI:1.120～4.091),post-occlusive brachial artery resistance index(OR=0.004,95%CI:0.000～0.140),and postoperative brachial flow(OR=1.004,95%CI:1.002～1.007).model1 demonstrated excellent discrimination(AUC=0.869,95%CI:0.817～0.921)and calibration(mean absolute error=0.017).DCA showed superior net benefit at 0.1～1.0 threshold probabilities.Compared with model1,non-significant improvements in AUC and IDI,while model4 achieved significant NRI improvements(P<0.05).Conclusion The prediction performance of AVF natural maturity prediction models constructed with 2DGLS,3DGLS,3DEF,or 2DEF is relatively high;The NRI of the model involving 3DEF is better than that of the model involving 2DEF,indicating that it may have better clinical application value within a specific threshold probability range.

Aim To investigate the effects of 2-dode-cyl-6-methoxycyclohexa-2 , 5-diene-l, 4-dione ( DM-DD) on resisting hepatic fibrosis induced by carbon tetrachloride ( CC14 ) in rats and the underlying mechanisms , with a specific focus on the TGF-pi/Smads signaling pathway. Methods The hepatic fibrosis model was replicated using 50% CC14. Various parameters, including levels of aspartate transferase ( AST) , ala-nine transferase ( ALT ) , albumin/globulin ( A/G ) , total protein (TP) , total bilirubin (T-BIL) , hyaluron-ic acid ( HA ) , laminin ( LN ) , collagen type Ж ( Col Ж) , and collagen type IV(ColIV) in the blood, were measured. Liver tissue lesions and fiber formation were observed using HE and Masson staining. The expression levels of a smooth muscle actin (a-SMA) , collagen type I ( Col I ) , transformed growth factor (TGF-pi), Smad2, and Smad7 proteins were assessed using immunohistochemistry. a-SMA, Coll, TGF-pi, and Smad7 mRNA levels in liver tissue were measured by RT-PCR. Additionally, the expression levels of TGF-pi, Smad4, and Smad7 proteins in liver tissue were determined by Western blot. Results In comparison to the normal control group, the model group exhibited significantly elevated levels of AST, ALT, TP, T-BIL, HA, LN, Col Ш and Col IV in serum. But A/G level notably decreased. Successful modeling was confirmed by the presence of extensive fiber formations observed through HE and Massonstaining in liver tissue. The DMDD administration group demonstrated a notable decrease levels of AST, ALT, TP, T-BIL, HA, LN, Col III, and CollV, but A/G was significantly elevated when compared to the model group. Furthermore, a-SMA, Coll, TGF-f31, Smad2 and Smad4 mRNA and protein levels in the DMDD administration group were significantly reduced, while Smad7 significantly declined. HE and Masson staining results reflected a marked reduction in fibrous hyper-plasia. Conclusion DMDD exhibits a protective effect against CCl4-induced hepatic fibrosis, and its mechanism appears to be associated with the TGF-fJl/ Smads signaling pathway.

Humans ; Vascular Stiffness ; Coal Mining ; Occupational Diseases/epidemiology* ; Risk Factors ; Coal ; Miners

Objective:To summarize and analyze the composition characteristics and problems of basic medical insurance policies for traditional Chinese medicine in various provinces of China,providing reference for optimizing and improving subsequent basic medical insurance policies for traditional Chinese medicine.Methods:Based on the perspective of policy instrument,combined with two dimensions of policy instrument types and policy development process,the content analysis method is used to quantitatively analyze the content of the basic medical insurance policies for traditional Chinese medicine released at the provincial level from 2011 to 2023.Results:The 93 included policy documents were coded and sorted,with a cumulative total of 487 codes.From the perspective of policy instrument dimensions,subcategories of policy instruments involve diverse themes,but there are differences in the level of attention paid to each policy tool.From the perspective of policy development process,each link also presents a discrete trend,indicating a dominant feature of policy planning and implementation.Conclusion:To improve the basic medical insurance policy system of traditional Chinese medicine in China,it is necessary to optimize the combination of policy instrument and construct a coordinated and balanced policy instrument framework;Overall planning of the development process of traditional Chinese medicine medical insurance policies,highlighting the unique advantages of traditional Chinese medicine;Emphasize policy synergy between dimensions and strengthen the implementation of traditional Chinese medicine medical insurance policies.

Objective:To investigate the intention to stay on among primary health care workers (PHWs) during the COVID-19 epidemics and its influencing factors.Methods:An online questionnaire survey was conducted among PHWs from 62 primary health institutions in 31 provinces, autonomous regions and municipalities across China selected by multi-stage whole cluster random sampling method between May and October 2022. According to the job position, the PHWs were divided into 5 categories: general practitioners (GPs), nurses, public health doctors, managers and support staff. Intention to stay was measured using the Chinese version of the Intention to Stay Questionnaire. Multiple linear regression model was used to analyze the influencing factors of the intention to stay in PHWs of different occupational categories, including personal factors, work factors, factors related to the COVID-19 and psychological reactions.Results:A total of 3 769 PHWs from 44 community health service centers, 18 township hospitals of 27 provinces/autonomous regions and 4 municipalities participated in this survey. The mean age of participants was (37.4±9.2) years, including 2 971(78.8%) women. The mean score of intention to stay of participants was 21.7±4.1. Compared with GPs, managers had lower intention to stay ( P=0.004). Age, female, in marriage, monthly income, years of primary care service, self-evaluation of unit support function, MSQ-SF score, and PA score were positively correlated with the score of intention to stay (all P<0.05), while PHQ-9 score, EE score, and DP score were negatively correlated with the score of intention to stay (all P<0.05). The MSQ-SF scores of all occupational categories were positively correlated with the scores of intention to stay (all P<0.01). In addition, among GPs, monthly income, years of service in primary care, self-evaluation of unit support function, and PA scores were positively correlated with the score of intention to stay (all P<0.05), while PHQ-9 scores and EE scores were negatively correlated with the score of intention to stay (all P<0.05). Among nurses, age, female gender, monthly income, self-evaluation of unit support function, and PA score were positively correlated with the score of intention to stay (all P<0.05), while EE scores and retention will score were negatively associated with ( P<0.001). Among public health doctors, in marriage was positively correlated with the score of intention to stay ( P=0.018). Among managers, DP score was negatively correlated with the score of intention to stay ( P=0.001). Among support staff, female gender, monthly income, years of primary care service, self-evaluation of unit support function, and PA scores were positively correlated with the score of intention to stay (all P<0.05), while EE score and DP score were negatively correlated with intention to stay (all P<0.05). Conclusions:The intention to stay of PHWs in China during the COVID-19 was at an intermediate level, which was affected by many factors. Among them, job satisfaction was positively correlated with the intention to stay of all occupational categories, and the influencing factors of different occupational categories have some variations.

Objective:To discuss the effect of sialic acid-binding immunoglobulin-like lectin-15(Siglec15)derived from M2 tumor-associated macrophages(M2-TAMs)on promoting the malignant biological behavior of the esophageal squamous cell carcinoma(ESCC)through bioinformatics analysis,and to validate the findings through cell experiment.Methods:The Tumor Immune Estimation Resource(TIMER)online Database was used to analyze the expression differences and immune infiltration of Siglec15 in pan-cancer and adjacent normal tissues.Real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of Siglec15 mRNA in M2-TAMs and ESCC EC109 and KYSE150 cells.Based on the non-contact co-culture of M2-TAMs and ESCC cells,the following groups were set up,such as EC109/KYSE150 group,EC109/KYSE150+si-NC group(transfected with si-NC sequence),and EC109/KYSE150+si-Siglec15 group(transfected with si-Siglec15#1 and si-Siglec15#2 sequences).CCK-8 method was used to detect the proliferation activities of the cells in various groups;wound healing assay was used to detect the wound healing rates of the cells in various groups;Transwell chamber assay was used to detect the numbers of migration and invasion cells in various groups;flow cytometry was used to detect the apoptotic rates of the cells in various groups.Results:The bioinformatics analysis results showed that compared with adjacent normal tissue,the expression levels of Siglec15 mRNA in pan-cancer tissues such as esophageal cancer,colon cancer,and head and neck squamous cell carcinoma tissues were increased(P＜0.05 or P＜0.01),and the expression level of Siglec15 mRNA in esophageal cancer tissue was significantly positively correlated with the infiltration of the macrophages(P＜0.05).Compared with the EC109 cells and KYSE150 cells,the expression level of Siglec15 mRNA in M2-TAMs was significantly increased(P＜0.01).There was no significant difference in the proliferation rate of the cells among EC109/KYSE150 group,EC109/KYSE150+si-NC group,and EC109/KYSE150+si-Siglec15 group(P＞0.05).Compared with EC109/KYSE150 group,after treated for 24 and 48 h,the wound healing rate of the cells in EC109/KYSE150+si-NC group was increased(P＜0.01),the numbers of migration and invasion cells were increased(P＜0.05),and the apoptotic rate was decreased(P＜0.01).Compared with EC109/KYSE150+si-NC group,the wound healing rates of the cells in EC109/KYSE150+si-Siglec15#1 group and EC109/KYSE150+si-Siglec15#2 group were decreased(P＜0.05),the numbers of migration and invasion cells were decreased(P＜0.05),and the apoptotic rates of the cells had no significant difference(P＞0.05).Conclusion:Siglec15 derived from M2-TAMs may be a key factor in promoting the migration and invasion of the ESCC cells.

Background: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor (TSHR) gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype–phenotype relationships for most TSHR variants associated with CH remain unexplored. We aimed to identify TSHR variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between TSHR genotypes and clinical phenotypes. Methods: In total, 367 patients with CH were recruited for TSHR variant screening using whole-exome sequencing. The effects of the variants were evaluated by in-silico programs such as SIFT and polyphen2. Furthermore, these variants were transfected into 293T cells to detect their Gs/cyclic AMP and Gq/11 signaling activity. Results: Among the 367 patients with CH, 17 TSHR variants, including three novel variants, were identified in 45 patients, and 18 patients carried biallelic TSHR variants. In vitro experiments showed that 10 variants were associated with Gs/cyclic AMP and Gq/11 signaling pathway impairment to varying degrees. Patients with TSHR biallelic variants had lower serum TSH levels and higher free triiodothyronine and thyroxine levels at diagnosis than those with DUOX2 biallelic variants. Conclusions We found a high frequency of TSHR variants in Chinese patients with CH (12.3%), and 4.9% of cases were caused by TSHR biallelic variants. Ten variants were identified as loss-of-function variants. The data suggest that the clinical phenotype of CH patients caused by TSHR biallelic variants is relatively mild. Our study expands the TSHR variant spectrum and provides further evidence for the elucidation of the genetic etiology of CH.