Immunotherapy, including immune checkpoint inhibitors, tumor vaccine therapy, oncolytic virotherapy, and adoptive cell therapy, has made remarkably breakthroughs in the field of oncology. Immune checkpoint inhibitors, which block programmed death receptor 1 or programmed death ligand 1, have been included in the first-line clinical treatment for advanced solid tumors, such as non-small cell lung cancer and malignant melanoma. However, primary or secondary drug resistance in tumors severely limits the survival benefits for patients. Immune-related adverse reactions, such as pneumonia, hypothyroidism, hypophysitis, and myocarditis, also greatly affect the quality of life of patients. Fuzheng Jiedu Huayu is an important concept guiding the prevention and treatment of tumors with traditional Chinese medicine (TCM). It is also a curative principle and therapeutic TCM method to reduce the toxicity and enhance the efficacy of immunotherapy. This article summarizes the research progress of immunotherapy and discusses how TCM reduces the toxicity and enhances the efficacy of immunotherapy, hoping to provide a reference for the integrated treatment of tumors with TCM and immunotherapy.

ObjectiveThe theory of homotherapy for heteropathy is one of the classical rules in traditional Chinese medicine. Taking this theory as a breakthrough point， this study employed gas chromatography-mass spectrometry （GC-MS） to elucidate the mechanism underlying the therapeutic effects of Zhuyuwan on both intrahepatic cholestasis （IC） and ulcerative colitis （UC） from the viewpoint of serum metabolic homeostasis. MethodsThe rat models of α-naphthylisothiocyanate （ANIT）-induced cholestasis and 2，4，6-trinitro-benzenesulfonic acid （TNBS）-induced UC were treated with low （0.6 g·kg^-1） and high （1.2 g·kg^-1） doses of Zhuyuwan by gavage. In the experiment regarding IC， 24 Sprague-Dawley （SD） rats were randomly assigned into four groups： normal， ANIT model， low-dose Zhuyuwan， and high-dose Zhuyuwan. In the experiment regarding UC， 24 SD rats were randomly allocated into four groups： normal， TNBS model， low-dose Zhuyuwan， and high-dose Zhuyuwan. Firstly， the two disease models and the intervention effects of Zhuyuwan on the two diseases were evaluated based on serum levels of biochemical indicators ［alanine aminotransferase （ALT）， aspartate transaminase （AST）， γ-glutamyltranspeptidase （γ-GT）， and total bile acid （TBA）］， colon damage score， colon weight index， disease activity index， and histopathological changes in rats. Secondly， the rat serum samples were analyzed by gas chromatography-mass spectrometry （GC-MS） to screen the common core pathways of the two disease models， and the expression of core genes in the pathways was determined by Real-time PCR， on the basis of which the biological mechanism of the treatment of the two disease models by Zhuyuwan was ultimately elucidated. ResultsThe results of the experiment regarding IC showed that the ANIT model group had higher ALT， AST， γ-GT， and TBA levels than the normal group （P<0.01）. Compared with the ANIT model group， the low-dose Zhuyuwan group showed declined ALT and TBA levels （P<0.01） and the high-dose Zhuyuwan group showed lowered ALT， TBA， AST， and γ-GT levels （P<0.01）. The results of the experiment regarding UC showed that compared with the normal group， the TNBS model group presented increases in the colonic damage score， colon weight index， and disease activity index （P<0.01）. Compared with the TNBS model group， the low-dose Zhuyuwan group showcased declines in colon weight index （P<0.01） and disease activity index （P<0.05）， and the high-dose Zhuyuwan group showed reductions in the colon damage score， colon weight index， and disease activity index （P<0.01）. GC-MS metabolomics analysis combined with qRT-PCR demonstrated that Zhuyuwan had a similar inverse regulatory effect on arginine metabolism disruption in the above two disease models. ConclusionZhuyuwan exhibited definite therapeutic effects on both IC and UC， and the regulation of arginine biosynthesis pathway is the core mechanism for the treatment of both diseases by Zhuyuwan.

ObjectiveThe theory of homotherapy for heteropathy is one of the classical rules in traditional Chinese medicine. Taking this theory as a breakthrough point， this study employed gas chromatography-mass spectrometry （GC-MS） to elucidate the mechanism underlying the therapeutic effects of Zhuyuwan on both intrahepatic cholestasis （IC） and ulcerative colitis （UC） from the viewpoint of serum metabolic homeostasis. MethodsThe rat models of α-naphthylisothiocyanate （ANIT）-induced cholestasis and 2，4，6-trinitro-benzenesulfonic acid （TNBS）-induced UC were treated with low （0.6 g·kg^-1） and high （1.2 g·kg^-1） doses of Zhuyuwan by gavage. In the experiment regarding IC， 24 Sprague-Dawley （SD） rats were randomly assigned into four groups： normal， ANIT model， low-dose Zhuyuwan， and high-dose Zhuyuwan. In the experiment regarding UC， 24 SD rats were randomly allocated into four groups： normal， TNBS model， low-dose Zhuyuwan， and high-dose Zhuyuwan. Firstly， the two disease models and the intervention effects of Zhuyuwan on the two diseases were evaluated based on serum levels of biochemical indicators ［alanine aminotransferase （ALT）， aspartate transaminase （AST）， γ-glutamyltranspeptidase （γ-GT）， and total bile acid （TBA）］， colon damage score， colon weight index， disease activity index， and histopathological changes in rats. Secondly， the rat serum samples were analyzed by gas chromatography-mass spectrometry （GC-MS） to screen the common core pathways of the two disease models， and the expression of core genes in the pathways was determined by Real-time PCR， on the basis of which the biological mechanism of the treatment of the two disease models by Zhuyuwan was ultimately elucidated. ResultsThe results of the experiment regarding IC showed that the ANIT model group had higher ALT， AST， γ-GT， and TBA levels than the normal group （P<0.01）. Compared with the ANIT model group， the low-dose Zhuyuwan group showed declined ALT and TBA levels （P<0.01） and the high-dose Zhuyuwan group showed lowered ALT， TBA， AST， and γ-GT levels （P<0.01）. The results of the experiment regarding UC showed that compared with the normal group， the TNBS model group presented increases in the colonic damage score， colon weight index， and disease activity index （P<0.01）. Compared with the TNBS model group， the low-dose Zhuyuwan group showcased declines in colon weight index （P<0.01） and disease activity index （P<0.05）， and the high-dose Zhuyuwan group showed reductions in the colon damage score， colon weight index， and disease activity index （P<0.01）. GC-MS metabolomics analysis combined with qRT-PCR demonstrated that Zhuyuwan had a similar inverse regulatory effect on arginine metabolism disruption in the above two disease models. ConclusionZhuyuwan exhibited definite therapeutic effects on both IC and UC， and the regulation of arginine biosynthesis pathway is the core mechanism for the treatment of both diseases by Zhuyuwan.

Gliomas are the most common primary neuroepithelial tumors of the central nervous system in adults, of which glioblastoma is the deadliest subtype. Apart from the intrinsically indestructible characteristics of glioma (stem) cells, accumulating evidence suggests that the tumor microenvironment also plays a vital role in the refractoriness of glioblastoma. The primary functions of platelets are to stop bleeding and regulate thrombosis under physiological conditions. Furthermore, platelets are also active elements that participate in a variety of processes of tumor development, including tumor growth, invasion, and chemoresistance. Glioma cells recruit and activate resting platelets to become tumor-educated platelets (TEPs), which in turn can promote the proliferation, invasion, stemness, and chemoresistance of glioma cells. TEPs can be used to obtain genetic information about gliomas, which is helpful for early diagnosis and monitoring of therapeutic effects. Platelet membranes are intriguing biomimetic materials for developing efficacious drug carriers to enhance antiglioma activity. Herein, we review the recent research referring to the contribution of platelets to the malignant characteristics of gliomas and focusing on the molecular mechanisms mediating the interaction between TEPs and glioma (stem) cells, as well as present the challenges and opportunities in targeting platelets for glioma therapy.
Humans ; Glioma/metabolism* ; Blood Platelets/physiology* ; Brain Neoplasms/pathology* ; Tumor Microenvironment

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective To explore the current status of work-related quality of life among nurses at ob-stetric and gynecological specialty hospitals,analyze their latent profiles,and identify influencing factors.Methods Using convenience sampling,574 nurses from a tertiary-level obstetric and gynecological specialty hospital in Shijiazhuang,Hebei Province were selected as subjects.Questionnaires including the General Infor-mation Survey,Nurse Work-Related Quality of Life Scale-2(WRQoL-2),and Resilience Scale were adminis-tered.Latent profile analysis was performed to assess the level of work-related quality of life,with influencing factors of the latent profiles identified through univariate and logistic regression analyses.Results Work-re-lated quality of life levels among nurses at obstetric and gynecological specialty hospitals were classified into three latent profiles,low-level group(27.53%),medium-level group(45.81%),and high-level group(26.66%).Logistic regression analysis revealed that gender,position,satisfaction with current income,aver-age overtime hours,daily sleep duration,and resilience scale scores were influencing factors for the latent pro-files of work-related quality of life among nurses at obstetric and gynecological specialty hospitals(P<0.05).Conclusion Heterogeneity exists in work-related quality of life among nursing staff at obstetric and gyneco-logical specialty hospitals,with three distinct latent profiles.Nursing managers may classify nurses for man-agement according to profile-specific influencing factors to improve their work-related quality of life.

Objective To develop an endothelialized microfluidic chip model that simulates the spatial architecture and bioactivity of retinal vasculature,enabling thrombosis modeling and thrombolytic efficacy validation.Methods A tri-level microvascular network chip(300/200/100 μm diameters)with bifurcated architecture was fabricated using soft lithography.Human retinal microvascular endothelial cells(HRMECs)were perfused into channels,with endothelial coverage monitored via phase-contrast microscopy and F-actin staining.Cellular bioactivity was assessed using mitochondrial membrane potential probes(5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide,JC-1)and nitric oxide(NO)quantification.Fresh blood samples from 10 healthy donors(Yongchuan Hospital Affiliated to Chongqing Medical University,March to June 2024)were perfused with digital injection pump to mimic blood flow in human body into 3 experimental groups:normal whole blood,and TNF-α-activated endothelium+normal blood,TNF-α-activated endothelium+TNF-α-treated blood.Three inlet blood flow rates of 37.8、11.1 and 3.5 μL/min were set in each group.Two experimental groups,normal saline and recombinant human tissue-type plasminogen activator(rtPA),were established using the endothelialized microfluidic thrombosis model to validate thrombolytic efficacy.Endothelial functional impacts were assessed through integrated DAPI/NO staining and thrombosis model analysis across 3 intervention phases:pre-thrombosis,post-thrombosis,and post-thrombolysis.Results A tri-level microfluidic vascular model(300/200/100 μm diameters)was successfully constructed.In 72 h after endothelial cell perfusion,complete channel coverage was achieved,with phase-contrast microscopy and F-actin staining confirming confluent cellular alignment.JC-1/NO assays validated preserved endothelial bioactivity.Compared with the whole blood group,both TNF-α-activated endothelium+normal blood and TNF-α-activated endothelium+TNF-α-treated blood groups exhibited significantly increased thrombus occupancy rates at identical flow rates(all P<0.001).Notably,TNF-α-activated endothelium+TNF-α-treated blood group demonstrated the highest thrombus ratio at 3.5 μL/min(P<0.001).The rtPA group showed superior thrombolytic efficacy versus saline(P<0.001).Endothelial monolayer integrity was maintained across intervention phases,with thrombosis triggering significant NO elevation(P<0.001).Conclusion Our retinal vasculature-mimetic microfluidic model enables precise thrombosis modeling and drug evaluation,providing new methodology for studying retinal vascular occlusive diseases.

Helicobacter pylori(H.pylori)infection triggers gastric mucosal inflammatory responses and spasmolytic polypeptide-expressing metaplasia(SPEM).These pathological conditions can escalate the severity of chronic gas-tritis,gastric ulcers and even cause gastric cancer.SPEM is frequently viewed as an early sign of gastric mucosal injury and the onset of carcinogenesis.A comprehensive analysis of the genesis and molecular regulation of SPEM cells in the context of H.pylori infection further has enlightened the pathogenesis of gastric mucosal diseases and provide new ideas and targets for diagnosing and treatment of H.pylori-related gastric mucosal diseases.This paper reviews a variety of molecular biomarkers associated with SPEM,encompassing TFF2,CD44v9,and AQP5,and delineates their pivotal regulatory functions in H.pylori infection and SPEM.This paper also reviews the origination of SPEM cells and pertinent molecular regulatory mechanisms.

Objective To compare the effect of routine speech training and computer-assisted training on post-stroke dysarthria. Methods From March,2021 to April,2023,72 patients with post-stroke dysarthria in Beijing Bo'ai Hospital were ran-domly divided into control group(n=36)and experimental group(n=36).Both groups received routine rehabili-tation,while the control group received routine speech training,and the experimental group received computer-assisted training,for four weeks.They were assessed with modified Frenchay Dysarthria Assessment(m-FDA)and Speech Intelligibility(SI)before and after intervention. Results Eight cases in the control group and one case in the experimental group dropped down.The scores of m-FDA and SI improved in both groups after treatment(|Z|＞4.183,P＜0.001),and there was no significant difference between two groups(|Z|＜1.598,P＞0.05).Noninferiority of m-FDA was found between two groups(|t|＞3.656,P＜0.001). Conclusion Computer-assisted training could improve the speech function of patients with post-stroke dysarthria,simi-lar to routine speech training.

Objective To observe the value of radiomics models based on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid(Gd-EOB-DTPA)enhanced hepatobiliary phase(HBP)MRI for assessing clinical pathological stage of hepatic fibrosis(HF).Methods Data of 240 patients with pathologically/clinically diagnosed and clinical pathological staged HF who underwent Gd-EOB-DTPA enhanced MR examination were retrospectively analyzed.The liver-to-muscle signal intensity ratio(SIR1)and liver-to-spleen signal intensity ratio(SIR2)were measured based on HBP images.Radiomics features of HBP images were extracted and screened to construct radiomics models.The signal intensity ratio(SIR)-radiomics combined models were constructed based on SIR and radiomics signatures.Receiver operating characteristic(ROC)curves were drawn to evaluate the efficacy of each model for assessing clinical pathological stage of HF.Results The area under the curve(AUC)of SIR1 and SIR2 models for assessing clinical pathological stage of HF were 0.63-0.70 and 0.65-0.71,respectively.The most effective radiomics model for assessing HF,significant HF,advanced HF and early cirrhosis was support vector machine(SVM),SVM,light gradient boosting machine and K-nearest neighbor model,respectively,with the AUC in validation set of 0.87,0.82,0.81 and 0.80,respectively,while the AUC of SIR-radiomics combined models in validation set of 0.88,0.82,0.82 and 0.81,respectively.Conclusion The radiomics models based on Gd-EOB-DTPA enhanced HBP MRI were helpful for assessing clinical pathological stage of HF.Combining with HBP SIR could improve their efficacy.