Immunotherapy has become a pivotal modality in clinical cancer treatment. However, its effectiveness is limited to a small subset of patients due to the low antigenicity, impaired innate response, and various adaptive immune resistance mechanisms of the tumor microenvironment (TME). Accumulating evidence reveals the critical roles of metal elements in shaping immunity against tumor progression and metastasis. The marriage of metalloimmunotherapy and nanotechnology further presents new opportunities to optimize the physicochemical and pharmacokinetic properties of metal ions in a precise spatiotemporal control manner. Several metallodrugs have demonstrated encouraging immunotherapeutic potential in preliminary studies and are currently undergoing clinical trials at different stages, yet challenges persist in scaling up production and addressing long-term biosafety concerns. This review delineates how metal materials modulate biological activities across diverse cell types to orchestrate antitumor immunity. Moreover, it summarizes recent progress in smart drug delivery-release systems integrating metal elements, either as cargo or vehicles, to enhance antitumor immune responses. Finally, the review introduces current clinical applications of nanomedicines in metalloimmunotherapy and discusses potential challenges that impede its widespread translation into clinical practice.

Objective:To explore the risk factors of short-term prognosis of severe Budd-Chiari syndrome (BCS) patients,established and verified the nomogram prediction model for these BCS patients and evaluated its clinical application value.Methods:This study is a retrospective cohort study. The clinical data of 171 patients with severe BCS diagnosed were retrospectively analyzed in the Department of Hepatopancreatobiliary Surgery First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023. There were 105 males and 66 females, aged (52.1±12.8) years (range: 18 to 79 years). The patients were divided into two groups based on whether they died within 28 days: the death group ( n=38) and the survival group ( n=133). The risk factors for short-term death of patients were analyzed,and independent risk factors were screened by univariate and multivariate analysis. Furthermore,these factors were used to establish the nomogram prediction model. The area under the curve(AUC),the Bootstrap Resampling,the Hosmer-Lemeshow test and the Decision Curve Analysis(DCA) were used to verify the model′s differentiation,internal verification,calibration degree and clinical effectiveness,respectively. Results:Univariate and multivariate Logistics regression analysis showed that the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time were independent risk factors ( P<0.05). The above factors were used to successfully establish the prediction model with 0.908 of AUC and 0.895 of the internal verification of AUC,indicating that the predictive model was valuable. The 0.663 P-values in the Hosmer-Lemeshow test indicated the high calibration degree of the model. The clinical effectiveness of the model was proved by the 18% clinical benefit population using the DCA curve with the 17% probability threshold. Conclusions:The independent risk factors are the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time. An adequate basis was acquired by establishing a nomogram prediction model of the short-term prognosis of severe BCS,which was helpful for early clinical screening and identification of high-risk patients with severe BCS who could die in the short term and timely providing timely intervention measures for improving the prognosis.

Objective:To explore the risk factors of short-term prognosis of severe Budd-Chiari syndrome (BCS) patients,established and verified the nomogram prediction model for these BCS patients and evaluated its clinical application value.Methods:This study is a retrospective cohort study. The clinical data of 171 patients with severe BCS diagnosed were retrospectively analyzed in the Department of Hepatopancreatobiliary Surgery First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023. There were 105 males and 66 females, aged (52.1±12.8) years (range: 18 to 79 years). The patients were divided into two groups based on whether they died within 28 days: the death group ( n=38) and the survival group ( n=133). The risk factors for short-term death of patients were analyzed,and independent risk factors were screened by univariate and multivariate analysis. Furthermore,these factors were used to establish the nomogram prediction model. The area under the curve(AUC),the Bootstrap Resampling,the Hosmer-Lemeshow test and the Decision Curve Analysis(DCA) were used to verify the model′s differentiation,internal verification,calibration degree and clinical effectiveness,respectively. Results:Univariate and multivariate Logistics regression analysis showed that the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time were independent risk factors ( P<0.05). The above factors were used to successfully establish the prediction model with 0.908 of AUC and 0.895 of the internal verification of AUC,indicating that the predictive model was valuable. The 0.663 P-values in the Hosmer-Lemeshow test indicated the high calibration degree of the model. The clinical effectiveness of the model was proved by the 18% clinical benefit population using the DCA curve with the 17% probability threshold. Conclusions:The independent risk factors are the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time. An adequate basis was acquired by establishing a nomogram prediction model of the short-term prognosis of severe BCS,which was helpful for early clinical screening and identification of high-risk patients with severe BCS who could die in the short term and timely providing timely intervention measures for improving the prognosis.

Abstract: Cancer immunotherapy, which is an attractive strategy harnessing the host's own immune system to remove tumor cells, has been widely used in clinical practice, yet with low response rate and immune-related adverse events. Unlike traditional chemotherapy, the targets of immunotherapy exhibit high spatial heterogeneity and are distributed in different cell types or secondary organelles, resulting in off-target and on-target toxicity, which greatly reduces the efficacy and safety of treatment. Due to the altered metabolic level, tumor tissues often display a lower pH than normal tissues. In addition, the endocytosis pathway is accompanied by continuous pumping of protons. Therefore, the variation of environmental pH values could serve as an ideal stimulus for precise drug delivery and release. In recent years, pH-responsive materials (e.g., polymers, biomacromolecules, lipid nanoparticles, biofilm, inorganic nanoparticles, and metal-organic frameworks) have been widely investigated in the field of cancer immunotherapy. This paper summarizes recent strategies of pH-responsive drug delivery systems based on different types of carriers, aiming to provide some reference for the design of next generation of tumor-targeting formulations in cancer immunotherapy.

Objective:To investigate the predictive value of controlled nutritional status (CONUT) score for overt hepatic encephalopathy (OHE) after transjugular intrahepatic portosys-temic stent-shunt (TIPSS) in Budd-Chiari syndrome patients.Method:The retrospective case-control study was conducted. The clinicopathological data of 48 Budd-Chiari syndrome patients who underwent TIPSS in the First Affiliated Hospital of Zhengzhou University from August 2014 to March 2021 were collected. There were 26 males and 22 females, aged (46±13)years. Observation indicators: (1) surgical situations and follow-up; (2) analysis of influencing factors of OHE after TIPSS; (3) predic-tion of OHE after TIPSS. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was performed using the t test. Measurement data with skewed distribution were represented by M( Q1, Q3), and comparison between groups was performed using the Mann-Whitney U test. Count data were expressed as absolute numbers or percentages, and comparison between groups was performed using the chi-square test or Fisher exact probability. Multivariate analysis was performed using the Logistic regression model with forward method. The receiver operating characteristic (ROC) curve was drawn and the area under the curve (AUC) was calculated to evaluate the efficacy. Comparison among AUC was performed using the Delong test. Results:(1) Surgical situations and follow-up. All 48 patients underwent TIPSS successfully, and the operation time of the 48 patients was (131±29)minutes. All patients were implanted with 8 mm covered stent. All 48 patients were followed up for 46(25,71)months, and there were 14 cases with OHE and 34 cases without OHE after TIPSS. Of the 14 cases with OHE, 12 cases were evaluated as West-Haven Ⅱ grade and 2 cases were evaluated as West-Haven Ⅲ grade. (2) Analysis of influencing factors of OHE after TIPSS. Results of multivariate analysis showed that history of hepatic encephalo-pathy and CONUT score were independent factors influencing the incidence of OHE of Budd-Chiari syndrome patients who underwent TIPSS ( odds ratio=8.36, 1.74, 95% confidence interval as 1.02?68.75, 1.12?2.69, P<0.05). (3) Prediction of OHE after TIPSS. Results of ROC curve showed that the AUC of the CONUT score, the Child-Pugh score of liver function and the integrated model of end-stage liver disease (iMELD) score in predicting the incidence of OHE after TIPSS was 0.77(95% confidence interval as 0.64?0.91, P<0.05), 0.71(95% confidence interval as 0.56?0.87, P<0.05) and 0.71(95% confidence interval as 0.53?0.88, P<0.05), respectively, and there was no significant difference between the AUC of the CONUT score and the Child-Pugh score of liver function or the iMELD score ( Z=0.84, 0.59, P>0.05). The optimal cutoff value of CONUT score in predicting the incidence of OHE after TIPSS was 7, with the sensitivity, specificity and Yodon index as 78.6%, 61.8% and 0.40, respectively. Conclusion:The CONUT score can be used to predict the incidence of OHE in Budd-Chiari syndrome patients who underwent TIPSS, and the discrimination of CONUT score is equivalent to the Child-Pugh score of liver function and the iMELD score.

Objective:To investigate the clinical treatment options for cavernous transformation of portal vein (CTPV).Methods:Data of 65 CTPV patients receiving invasive treatment and followed up at the First Affiliated Hospital of Zhengzhou University between Apr 2011 and Apr 2021 were collected. Patients were divided into four groups based on different treatment option, 24 patients were treated with transjugular intrahepatic portosystemic stent-shunt (TIPS) and 11 patients with splenopneumopexy, while 22 patients underwent splenectomy and devascularization , 8 were treated by endoscopic variceal ligation . The difference of postoperative upper gastrointestinal bleeding and hepatic encephalopathy between the four groups were analyzed,Results:There were no difference between four groups in sex, age, preoperative serum aspartate aminotransferase, total bilirubin, albuminand Child-Turcotte-Pugh grade. The incidence of hepatic encephalopathy in the TIPS group was 33.3%±9.6%、46.5%±10.3% and 64.4%±13.1% in half year, 1 year, and 3 years , respectively. Postoperative hepatic encephalopathy rate was higher in TIPS group( χ2=31.191, P=0.000). Three patients in the TIPS group developed upper gastrointestinal hemorrhage within 6 months after the operation, and postoperative upper gastrointestinal bleeding rate was higher in splenopneumopexy group( χ2=7.542, P=0.006), Conclusion:The clinical treatment options for CTPV patients are complicated ,we should make individual treatment options depend on the etiology, clinical symptoms and site of blood flow obstruction.

OBJECTIVE To explore the establishment of standardized training system for medication direction provided by pediatric pharmacists. METHODS Based on the questionnaire， the current needs of pediatric pharmacists and parents of children for medication direction were investigated， and the standardized training content of pediatric medication direction was constructed as a whole with reference to the survey results， instructions， databases and other literature. The basic knowledge of medication direction was integrated and summarized from the basic information of drugs such as drug name， usage and dosage， as well as the course of treatment， order of medication and special precautions， so as to form the general introduction of training content. In accordance with the principle of “integrated drug classification based on diseases”， a standardized framework of medication direction for various common diseases in children was constructed to form various theories of training content. Concomitantly， the pilot training of pharmacists in Qingdao Women and Children’s Hospital of Qingdao University was carried out， and the training effect was preliminarily evaluated. RESULTS After standardized training， the daily examination scores of pharmacists in this hospital were significantly higher than those before training， and the situation of ‘0’ times of receiving patients’ thank-you letters in the window service was broken through； the effective satisfaction rate of window service showed an increasing trend； after the pharmacist explained the medication to the patient， the times of patient returning to consult the doctor on how to use the medicine showed downward trend. CONCLUSIONS The establishment and implementation of a systematic standardized training system for pediatric-specialist pharmacists can help to further improve the professional skills and professionalism of pharmacists， strengthen the standardization of window medication direction and enhance patients’ sense of gain.

OBJECTIVE To systematically evaluate the clinical efficacy and safety of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis. METHODS Randomised controlled trials on pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis which were publicly published in Chinese and English were searched from CNKI， Wanfang， VIP， PubMed， Cochrane library and other databases. The search time was set from January 2000 to December 2021. The existing studies were combined with indirect meta-analysis to systematically evaluate the efficacy and safety of the two drugs in the treatment of idiopathic pulmonary fibrosis. RESULTS A total of 15 randomized controlled trials were included， involving 1 026 cases in trial group of pirfenidone and 845 cases in control group of pirfenidone， 1 846 cases in trial group of nintedanib and 1 848 cases in control group of nintedanib. Both control groups were placebo. The results of indirect meta-analysis showed that the two drugs were similar in the evaluation indicators of therapeutic efficacy as acute exacerbation rate， the incidence of forced vital capacity （FVC）% decrease ≥10% from baseline or the incidence of absolute value decrease ≥0.2 L （P values of indirect analysis results were all ＞ 0.01， and the difference was not statistically significant）； but in terms of disease progression rate， nintedanib 150 mg （bid） was superior to pirfenidone 800 mg （tid） （RR＝1.66， 95%CI＝1.06-2.63）； in terms of safety， the incidence of diarrhea induced by nintedanib 150 mg （bid） was higher than pirfenidone 800 mg （tid） （RR＝0.42， 95%CI＝0.33-0.53）. CONCLUSIONS Compared with pirfenidone， nintedanib has slightly superior efficacy in terms of disease progression control， but the incidence of adverse reactions is also increased.

Objective:To explore the mechanism of mTOR/HIF-1α signaling pathway in Budd-Chiari syndrome (B-CS) liver fibrosis.Methods:Twenty male C57 mice were randomly divided into Sham operation group (Sham), sham operation+ rapamycin (Sham+ Ra) group, B-CS group, B-CS+ rapamycin (B-CS+ Ra) Group, 5 in each group. The B-CS mouse model was constructed by partial ligation of the inferior vena cava(IVC) at the posterior segment of the liver; IVC was not ligated in the Sham group. Mice in Sham+ Ra and B-CS+ Ra groups were intraperitoneally injected with rapamycin (2 mg/kg, 5% DMSO solution preparation) every other day, Sham group and B-CS group were injected with the same dose of 5% DMSO solution.After 6 weeks, samples were taken, and part of the liver tissue was used to make paraffin sections for hematoxylin-eosin (HE) and Sirus Red staining to observe the pathological changes, and immunohistochemical staining to detect the expression of α-SMA and Fibrinogen in liver tissues; Protein and RNA were extracted from fresh liver tissue, and Western-blot was used to detect α-SMA, Fibrinogen, p-mTOR, mTOR, HIF-1α, Collagen I, and VEGF protein levels. Real-time fluorescent quantitative PCR was used to detect mTOR, HIF-1α, CollagenⅠ, VEGF mRNA levels.Measurement data were expressed as mean±standard deviation ( ± s), and the comparison between groups was performed by one-way ANOVA test. Results:The results of pathological staining showed that in the B-CS group, there was severe congestion around the central vein of the liver and sinusoids, widening of the sinus space, and increased collagen deposition, indicating that this study successfully established a mouse B-CS liver fibrosis model. The expression levels of fibrosis indicators α-SMA and Collagen I protein, mTOR pathway related indicators p-mTOR and HIF-1α protein, and microthrombus indicator Fibrinogen protein in the Sham group were 0.027±0.012, 0.337±0.008, 0.138±0.024, 0.296±0.113, 0.733±0.192; B-CS group were 0.986±0.001, 0.927±0.055, 0.936±0.044, 1.693±0.443, 1.612±0.068, and the differences were statistically significant ( P<0.05). The expression levels of B-CS+ Ra group were 0.707±0.078, 0.311±0.024, 0.332±0.094, 0.254±0.117, 0.569±0.075, which were statistically significant compared with B-CS group ( P<0.05). Conclusions:The mTOR/HIF-1α signaling pathway is significantly activated in mouse B-CS liver fibrosis. This pathway may participate in the development of liver fibrosis by regulating microthrombosis.

Objective:To understand the current situation of cognitive dysfunction in patients with coronary heart disease, and explore the risk prediction model of the onset of cognitive dysfunction in patients with coronary heart disease.Methods:A total of 448 patients with coronary heart disease admitted to the North China University of Science and Technology Affiliated Hospital from January 2019 to June 2020 were prospectively selected as study subjects. Patients with coronary heart disease were divided into the cognitive dysfunction group ( n=185) and the normal cognitive function group ( n=263) according to whether they were accompanied by cognitive dysfunction. Demographic characteristics, cognitive function, disease history, blood pressure, blood glucose, blood lipid and vascular lesions were compared between the two groups. Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive function. Logistic regression was used to analyze the risk factors of cognitive dysfunction in coronary heart disease patients, and the prediction model of the above risk factors was constructed. The value of the prediction model was evaluated by C-index and cilibration curve. Results:The language, abstraction, visual space and execution, delayed memory and total scores of the cognitive dysfunction group were 1.81 ± 0.59, 1.12 ± 0.33, 3.01 ± 0.90, 2.61 ± 0.79 and 22.32 ± 1.70, respectively, which were lower than those of the normal cognitive function group (2.68 ± 0.47, 1.82 ± 0.38, 4.54 ± 0.50, 4.77 ± 0.42, 27.67 ± 0.76), and the differences were statistically significant ( t values were 17.39-40.00, all P<0.05). The age, fasting blood glucose, systolic blood pressure, proportion of alcohol drinking, proportion of diabetes mellitus in the cognitive dysfunction group were (62.86 ± 5.21) years, (6.19 ± 0.89) mmol/L, (144.00 ± 17.16) mmHg (1 mmHg=0.133 kPa), 36.76% (68/185), 16.22% (30/185), respectively, which were higher than (58.77 ± 5.63) years, (5.46 ± 0.95) mmol/L, (133.74 ± 15.90) mmHg, 27.38% (72/263), 6.84% (18/263) in the normal cognitive function group, the differences were statistically significant ( t=7.81, 8.25, 6.42, χ2=4.45, 9.97, all P<0.05). The rates of single vessel, double vessel and three vessel lesions in the cognitive dysfunction group were 49.73% (92/185), 27.03% (50/185) and 23.24% (43/185), respectively, and those in normal cognitive function group were 46.39% (122/263), 39.92% (105/263) and 13.69% (36/263), respectively ( χ2=11.10, P<0.05) . Logistic regression analysis showed that age, fasting blood glucose, systolic blood pressure and number of vascular lesions were independent risk factors for coronary heart disease patients with cognitive impairment ( OR values were 1.038-2.216, all P<0.05). The correction curve of the prediction model composed of age, fasting blood glucose, systolic blood pressure and number of vascular lesions was in good agreement with the ideal curve, and the C-index of the model was 0.807 for the diagnosis of cognitive dysfunction in patients with coronary heart disease. Conclusions:The cognitive dysfunction of patients with coronary heart disease is mainly manifested in language, abstraction, visual space and execution and delayed memory. The prediction model composed of age, fasting blood glucose, systolic blood pressure and number of vascular lesions has a certain degree of discrimination and accuracy for patients with coronary heart disease complicated by cognitive dysfunction, and can be used for the screening of coronary heart disease complicated by cognitive dysfunction.