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 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.

Objective:To study the clinical value of the Naples prognostic score (NPS) in predicting the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) after radical resection and establish a nomogram prediction model.Methods:Clinical data of 77 patients with ICC undergoing radical hepatectomy for the first time in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022 were retrospectively collected, including 46 males and 31 females, aged (58.9±11.0) years old. The area under the receiver operating characteristic curve for NPS to predict the death after radical hepatectomy in ICC patients was 0.673, and the optimal cut-off value for NPS based on the Youden's index was 2.5. According to the optimal cut-off value of NPS, patients were divided into two groups: the low NPS group (patients with NPS≤2.5, n=37) and high NPS group (patients with NPS>2.5, n=40). The clinicopathological data including resection extent, blood transfusion, tumor differentiation, lymphovascular invasion, lymph node metastasis and postoperative complications were compared between the groups. Follow-ups were conducted via outpatient or telephone reviews. Kaplan-Meier method was used for survival analysis, and log-rank test was used for survival comparison. Cox proportional hazards regression was used to analyze the risk factors affecting postoperative survival. A prediction nomogram was established and evaluated. Results:Compared to the low NPS group, the proportion of patients with tumor length ≥5 cm, lymphovascular invasion, lymph node metastasis, tumor carbohydrate antigen 19-9 ≥37 U/ml and the level of neutrophil to lymphocyte ratio were increased in the high NPS group, while the proportion of patients with serum albumin ≥40 g/L was decreased (all P<0.05). The cumulative survival rate of patients in the high NPS group was lower than that of the low NPS group ( P=0.001). Multivariate Cox analysis showed that ICC patients with lymphovascular invasion, lymph node metastasis, and NPS>2.5 had a higher risk of short survival after surgery (all P<0.05). The nomogram model based on NPS has a good predictive capacity. Conclusion:High preoperative NPS score indicates poor postoperative prognosis, and NPS score is an independent risk factor affecting the prognosis of ICC patients.

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 effect of metformin on liver fibrosis in a mouse model of Budd-Chiari syndrome and its mechanism. Methods A total of 30 male C57 mice were randomly divided into sham-operation group (SHAM group) with 6 mice, sham operation+ metformin group (SHAM+M group) with 5 mice, Budd-Chiari model group (BCS group) with 10 mice, and Budd-Chiari model+metformin group (BCS+M group) with 9 mice. The mice in the model group were treated with partial ligation of the inferior vena cava, those in the SHAM group were not treated with ligation, and those in the metformin group were given 0.1% metformin in drinking water besides modeling. The mice were sacrificed after 6 weeks. HE staining and picrosirius red staining were used to observe liver histopathology and collagen deposition; immunohistochemistry was used to measure the expressions of α-smooth muscle actin (α-SMA) and fibrinogen; quantitative real-time PCR was used to measure the mRNA expression of hypoxia-inducible factor 1α (HIF-1α) and type Ⅰ collagen (collagen 1), and Western blot was used to measure the relative protein expression levels of HIF-1α, vascular endothelial growth factor (VEGF), fibrinogen, α-SMA, and collagen 1. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results Pathological staining showed that compared with the SHAM group, the BCS group had significant liver fibrosis, disordered arrangement of hepatocytes near the central vein, sinusoidal expansion with red blood cell deposition and a small amount of inflammatory cell infiltration, and collagen deposition. The BCS group had significant increases in the mRNA expression levels of HIF-1α and collagen 1 and the protein expression levels of α-SMA, collagen 1, HIF-1α, VEGF, and fibrinogen (all P < 0.05); compared with the BCS group, the BCS+M group had significant alleviation of liver fibrosis, red blood cell deposition, and collagen deposition and significant reductions in the mRNA expression levels of HIF-1α and collagen 1 and the protein expression levels of α-SMA, collagen 1, HIF-1α, VEGF, and fibrinogen (all P < 0.05). Conclusion Metformin can improve congestive liver fibrosis caused by Budd-Chiari syndrome, possibly by reducing microthrombus in hepatic sinusoid and inhibiting the HIF-1α/VEGF pathway.

Objective:To study the factors influencing short-term prognosis of patients with Budd-Chiari syndrome (B-CS) presenting with upper gastrointestinal bleeding and to assess the predictive value of platelet-albumin-bilirubin score (PALBI) on death within 30 d in these patients.Methods:A retrospective study was conducted on 74 patients with B-CS who presented with upper gastrointestinal bleeding and were treated at the First Affiliated Hospital of Zhengzhou University from January 2014 to February 2020. There were 51 males and 23 females, with age of (46.5±11.1) years old. These patients were divided into the survival group ( n=58) and the death group ( n=16) according to the disease outcomes up to 30 d of follow-up. Factors influencing short-term deaths of these patients were analyzed, and the predictive values of PALBI, ALBI, CTP and MELD scores on short-term prognosis of the patients were assessed. The receiver operating characteristic (ROC) curves were plotted, and the areas under the curve (AUC) were calculated and compared. Results:The differences between patients in the survival and death groups for white blood cell, platelet, PALBI score, PALBI classification, ALBI score, CTP score, MELD score, and presence or absence of hepatic encephalopathy were significantly different (all P<0.05). Multivariate logistic regression analysis showed that CTP score≥10 or CTP grade C ( OR=1.669, 95% CI: 1.048-2.661), and PALBI score >-2.09 or PALBI grade 3 ( OR=5.245, 95% CI: 2.128-12.924) were independent risk factors for predicting death within 30 days. The areas under the ROC curves for PALBI, ALBI, CTP and MELD score were 0.89, 0.72, 0.77 and 0.76, with the cut-off values of -1.92, -1.60, 8.50 and 13.60, respectively. The differences between the PALBI score and ALBI, CTP scores were significantly different ( P<0.05). Conclusion:The PALBI score showed a positive predictive value on short-term prognostic assessment of patients with B-CS presenting with upper gastrointestinal bleeding. It was comparable to the effect of the MELD score but was significantly better than the ALBI and CTP scores.

OBJEC TIVE To provide reference for clinical comprehensive evaluation of pediatric drugs in China. METHODS Taking pediatric anti-allergic drugs as an example ，the clinical comprehensive evaluation methods of pediatric drugs in medical institutions were explored from the aspects of theme selection ，evaluation content and dimension ，evaluation index ，evaluation method and evaluation result report. RESULTS & CONCLUSIONS During the clinical comprehensive evaluation of pediatric drugs，under the guidance of relevant national guidelines for clinical comprehensive evaluation ，the evaluation topics could be selected according to the three principles of importance ，relevance and evaluability ，and then an appropriate evaluation index system could be developed around the six dimensions of safety ， effectiveness， economy， suitability，accessibility and innovativeness；qualitative and quantitative data integration analysis of the drugs to be evaluated were performed. In the evaluation ， it is necessary to focus on children ’s clinical basic drug use practice and decision-making needs ，normatively，scientifically and reasonably define the core index set and standard data set required by different dimensions of evidence ，standardize the collection and use of real-world data ，and effectively combine other types of evidence to truly play its advantageous role in the clinical comprehensive evaluation of pediatric drugs in China.

Objective:To evaluate the effect of three teaching methods of case-based learning (CBL), problem-based learning (PBL) and blended learning (CBL+PBL) on the teaching of clinical clerkship of cardiovascular internal medicine among medical students.Methods:A total of 175 third-year medical students were divided into three groups (CBL, PBL and CBL+PBL). They entered the clinical clerkship in batches, and then received written examination and questionnaire survey after the teaching. The data were processed by SPSS 19.0 and were compared by one-way ANOVA or chi-square test (R × C) among groups.Results:The total average scores of students in CBL, PBL and CBL+PBL groups were 15.34±2.88, 14.67±2.98 and 17.13±2.82, respectively ( P<0.05), and the proportion of students with "excellent" scores were 27.4%(17/62), 14.5%(9/62) and 58.1%(36/162), respectively. Most students in CBL group did not agree that CBL helped to train literature access skills [70.7%(41/58)] or teamwork ability [82.8%(48/58)], compared with which 70.9%(39/55) in PBL group thought it helped to train literature access skills but only 7.3%(4/55) well accepted PBL. In addition, majority of students in CBL+PBL group believed it was helpful to gain learning interest [64.3%(36/56)] and train team cooperation ability [62.5%(35/56)], and [53.6%(30/56)] favored this teaching method. Conclusion:Compared with traditional CBL, PBL fails to attract students or improve teaching performance; while blended learning is benefited for the students and can improve teaching quality.

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.