Cancer immunotherapy has emerged as a promising strategy. However, low response rates and immune-related side effects have plagued immunotherapy. Metallic nanoparticles, utilizing metals as their framework, are gaining prominence in cancer immunotherapy. Metal ions have shown the ability to modulate immune status by activating the cGAS-STING pathway and inducing immunogenic cell death (ICD), thereby enabling multidimensional activation of immunotherapy. Metallic nanoparticles offer significant advantages in cancer immunotherapy, leading to their increasing use in enhancing therapeutic outcomes. In view of the ever-increasing research on metallic nanoparticles, this review presents the construction, characterization, and enhanced cancer immunotherapeutic effects of different types of metal nanosystems from the perspective of the immunoregulatory mechanisms of metal ions. We delve into the current limitations and future directions of metallic nanoparticles in this rapidly evolving field. To the best of our knowledge, this review offers the most up-to-date and systematic analysis of metallic nanoparticles in immunotherapeutic applications. It is anticipated that this review of metallic nanoparticles will inspire a more refined and intelligent design of metallic nanoparticles for future research, paving the way for advancing their clinical applications.

Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
Ferroptosis/drug effects* ; Humans ; Iron/metabolism* ; Glioblastoma/metabolism* ; Tumor Suppressor Protein p53/metabolism* ; Homeostasis/physiology* ; Ferritins/metabolism* ; Brain Neoplasms/genetics* ; Mutation ; Astrocytes/drug effects* ; Cell Line, Tumor ; Piperazines/pharmacology* ; Quaternary Ammonium Compounds/pharmacology* ; Ferric Compounds

OBJECTIVE To evaluate the efficacy， safety and cost-effectiveness of generic drugs and original drugs of voriconazole. METHODS The information of patients who used voriconazole generic drugs selected in National Centralized Drug Procurement （generic drug group） or non-selected original drugs （original drug group） in the treatment of fungal infection was collected from the our hospital. The propensity score matching was carried out to eliminate bias. The comprehensive efficacy was evaluated according to clinical efficacy， image findings and microbiological test， and stratified analysis of different populations was conducted based on fungal species， underlying diseases， etc.， the efficacy of different stratifications was evaluated. Evaluation of safety was performed by using the incidence of adverse reactions. The total cost， defined daily doses （DDDs） and defined daily dose cost （DDDc） were used to evaluate the cost-effectiveness. RESULTS A total of 436 patients were included， and there were 190 patients in each group after matching. In terms of efficacy， the effective rates of voriconazole generic drugs and original drugs were 62.63% and 59.47% （P＝0.528）； in terms of safety， the incidence of adverse reactions caused by generic drugs and original drugs of voriconazole was 13.68% and 7.89%， respectively（P＝0.069）. In terms of cost-effectiveness， the average total cost of generic drugs was 4 636.26 yuan， and that of original drugs was 8 613.20 yuan （P＜0.001）. After the implementation of National Centralized Drug Procurement， replacement rate of generic drugs increased to 87.30%， and DDDc decreased by 59.08%. CONCLUSIONS The efficacy and safety of voriconazole generic drugs are similar to those of original drugs in the treatment of fungal infection， and it is more cost-effective in terms of treatment cost.

ObjectiveTo observe the regulatory effect of Huangwu Ganfu ointment on transient receptor potential anchor protein 1 （TRPV1） receptor expression， macrophage polarization， and p38 mitogen-activated protein kinase （p38 MAPK） signaling pathway in synovial tissue of knee osteoarthritis （KOA） rats with yang deficiency and cold coagulation syndrome and explore the mechanism of relieving peripheral inflammatory hyperalgesia of KOA. MethodForty-eight male SD rats were randomly divided into blank group， model group， high-dose， middle-dose， and low-dose groups of Huangwu Ganfu ointment （9.3， 4.65， 2.325 g·kg^-1）， and celecoxib group （20.82 mg·kg^-1）. The KOA rat model of yang deficiency and cold coagulation syndrome was established through climate box and swimming for two weeks combined with an injection of sodium iodoacetate （MIA） in the articular cavity. After continuous administration for four weeks， the general condition of rats in each group was observed， and the pain withdrawal threshold （PWT） and joint diameter induced by mechanical stimulation were recorded. The expression levels of interleukin-1β （IL-1β）， tumor necrosis factor-α （TNF-α）， nerve growth factor （NGF）， and calcitonin gene-related peptide （CGRP） inflammatory factor were detected by enzyme-linked immunosorbent assay （ELISA）， and the histopathological changes of synovial tissue of the knee joint were observed by hematoxylin-eosin （HE） staining. Western blot was used to detect the protein expression of TRPV1， p38 MAPK， and p-p38 MAPK in synovial tissue of the knee joint， and immunofluorescence （IF） was used to evaluate the polarization of M1/M2 macrophages. ResultCompared with that in the blank group， the overall mental state of the model group was worse， and the autonomous activity was decreased. The body mass was lower， and the joint diameter was increased. The X-ray showed that the osteophyte at the edge of the joint proliferated， and the articular surface was obviously rough. The articular cavity was significantly narrowed， and the PWT was significantly decreased （P<0.01）. The contents of IL-1β， TNF-α， CGRP， and NGF in serum and synovium Krenn score increased significantly （P<0.01）. The protein expression of TRPV1 and p-p38 MAPK/p38 MAPK increased significantly （P<0.01）， and the proportion of M1 macrophages and M1/M2 increased （P<0.01）， while the proportion of M2 macrophages decreased （P<0.01）. Compared with model group， the body mass in the low， middle， and high dose groups of Huangwu Ganfu ointment increased to different degrees （P<0.05， P<0.01）. The diameter of the knee joint in the high dose group of Huangwu Ganfu ointment and celecoxib group decreased （P<0.01）. The recovery of PWT in the high and middle dose groups of Huangwu Ganfu ointment groups was more obvious （P<0.05）. The contents of IL-1β and CGRP in the serum of rats in each administration group were significantly decreased （P<0.01）， and the content of serum TNF-α in the celecoxib group and high dose group of Huangwu Ganfu ointment decreased significantly （P<0.05）. The content of serum NGF in the middle dose group of Huangwu Ganfu ointment decreased significantly （P<0.05）， and the synovium Krenn score decreased in the high dose group of Huangwu Ganfu ointment （P<0.05）. In addition， the protein expression of TRPV1 and p-p38 MAPK/p38 MAPK in synovial tissue decreased significantly in all groups of Huangwu Ganfu ointment （P<0.01）. The proportion of M1 macrophages in synovial tissue in the celecoxib group and all groups of Huangwu Ganfu ointment decreased （P<0.01）， and the proportion of M2 macrophages in the high dose group of Huangwu Ganfu ointment increased （P<0.05）. The M1/M2 in the middle and high dose groups of Huangwu Ganfu ointment decreased （P<0.05）. ConclusionHuangwu Ganfu ointment can mediate the polarization of macrophages to reduce the inflammatory reaction of KOA， alleviate the release of inflammatory pain mediators， and lower the protein expression of TRPV1. The mechanism may be related to the p38 MAPK signaling pathway， so as to improve the peripheral hyperalgesia of KOA.

Objective:To compare the recurrence of common bile duct stones (CBDS) in patients with gallstones and concurrent CBDS treated by two surgical approaches: synchronous laparoscopic cholecystectomy (LC) combined with laparoscopic common bile duct exploration (LCBDE) (LC+LCBDE) and synchronous LC combined with intraoperative endoscopic sphincterotomy (IO-EST) (LC+IO-EST).Methods:From Apr 2013 to Apr 2020, the clinical data of 903 patients with gallstones with CBDS who were admitted to the Clinical Medical College, Yangzhou University were retrospectively analyzed.Results:Based on the chosen surgical method, we categorized 389 cases into group A (LC+LCBDE) and 514 cases into group B (LC+IO-EST). Our findings revealed that group A had a significantly lower rate of CBDS recurrence and re-recurrent CBDS compared to group B (4.4% vs. 8.4%, P=0.024; 0.8% vs. 3.1%, P=0.010). Moreover, Logistic regression analysis after inverse probability of treatment weighting, revealed that the surgical approach implemented in group A was an independent protective factor of recurrent CBDS and second recurrence of CBDS ( OR=0.482, 95% CI: 0.365-0.637, P<0.001; OR=0.118, 95% CI:0.080-0.173, P<0.001). Conclusion:LC+LCBDE is an optimal treatment option to LC+IO-EST for patients with gallstones combined with CBDS and common bile duct ≥8 mm.

Objective:To analyze the risk factors related to the prognosis of patients with sepsis in intensive care unit (ICU), construct a nomogram model, and verify its predictive efficacy.Methods:A retrospective cohort study was conducted using data from Medical Information Mart for Intensive Care-Ⅳ 0.4 [MIMIC-Ⅳ (version 2.0)]. The information of 6 500 patients with sepsis who meet the diagnostic criteria of Sepsis-3 were collected, including demography characteristics, complications, laboratory indicators within 24 hours after ICU admission, and final outcome. Using a simple random sampling method, the patients were divided into a training set and a validation set at a ratio of 7∶3. The restricted cubic spline (RCS) was used to explore whether there was a linear relationship between each variable and the prognosis, and the nonlinear variables were truncated into categorical variables. All variables were screened by LASSO regression and included in multivariate Cox regression analysis to analyze the death risk factors in ICU patients with sepsis, and construct a nomograph. The consistency index, calibration curve and receiver operator characteristic curve (ROC curve) were used to evaluate the prediction efficiency of nomogram model. The decision curve analysis (DCA) was used to validate the clinical value of the model and its impact on actual decision-making.Results:Among 6 500 patients with sepsis, 4 551 were in the training set and 1 949 were in the validation set. The 28-day, 90-day and 1-year mortality in the training set were 27.73% (1?262/4?551), 34.76% (1?582/4?551), and 42.98% (1?956/4?551), respectively, those in the validation set were 27.24% (531/1?949), 33.91% (661/1?949), and 42.23% (823/1?949), respectively. Both in training set and the validation set, compared with the final survival patients, the death patients were older, and had higher sequential organ failure assessment (SOFA) score and simplified acute physiology scoreⅡ (SAPSⅡ), more comorbidities, less urine output, and more use of vasoactive drugs, kidney replacement therapy, and mechanical ventilation. By RCS analysis, the variables with potential nonlinear correlation with the prognosis risk of septic patients were transformed into categorical variable. The variables screened by LASSO regression were enrolled in the multivariate Cox regression model. The results showed that age [hazard ratio ( HR) = 1.021, 95% confidence interval (95% CI) was 1.018-1.024], SOFA score ( HR = 1.020, 95% CI was 1.000-1.040), SAPSⅡ score > 44 ( HR = 1.480, 95% CI was 1.340-1.634), mean arterial pressure (MAP) ≤ 75 mmHg (1 mmHg ≈ 0.133 kPa; HR = 1.120, 95% CI was 1.026-1.222), respiratory rate (RR; HR = 1.044, 95% CI was 1.034-1.055), cerebrovascular disease ( HR = 1.620, 95% CI was 1.443-1.818), malignant tumor ( HR = 1.604, 95% CI was 1.447-1.778), severe liver disease ( HR = 1.330, 95% CI was 1.157-1.530), use of vasoactive drugs within 24 hours ( HR = 1.213, 95% CI was 1.101-1.336), arterial partial pressure of oxygen (PaO 2; HR = 0.999, 95% CI was 0.998-1.000), blood lactic acid (Lac; HR = 1.066, 95% CI was 1.053-1.079), blood urea nitrogen (BUN) > 8.9 mmol/L ( HR = 1.257, 95% CI was 1.144-1.381), total bilirubin (TBil; HR = 1.023, 95% CI was 1.015-1.031), and prothrombin time (PT) > 14.5 s ( HR = 1.232, 95% CI was 1.127-1.347) were associated with the death of ICU patients with sepsis (all P < 0.05). Based on the above factors, a nomogram model was constructed, and the model validation results showed that the consistency index was 0.730. The calibration curve showed a good consistency between the predicted results of the nomogram model and observed results in the training and validation sets. ROC curve analysis showed that the area under the ROC curve (AUC) predicted by the nomogram model in the training set and the validation set for 28-day, 90-day and 1-year death risk was 0.771 (95% CI was 0.756-0.786) and 0.761 (95% CI was 0.738-0.784), 0.777 (95% CI was 0.763-0.791) and 0.765 (95% CI was 0.744-0.787), 0.677 (95% CI was 0.648-0.707) and 0.685 (95% CI was 0.641-0.728), respectively. DCA analysis showed that the nomogram model had significant net benefits in predicting 28-day, 90-day, and 1-year death risk, verifying the clinical value of the model and its good impact on actual decision-making. Conclusions:The death risk factors related to ICU patients with sepsis include age, SOFA score, SAPSⅡ score > 44, MAP ≤ 75 mmHg, RR, cerebrovascular disease, malignant tumors, severe liver disease, use of vasoactive drugs within 24 hours, PaO 2, Lac, BUN, TBil, PT > 14.5 s. The nomogram model constructed based on this can predict the death risk of ICU patients with sepsis.

Objective To develop an accurate,rapid and sensitive flow cytometry method for the determination of anti-mesenchymal stem cell antibody in cynomolgus monkey serum.Methods After the solutions of mesenchymal stem cell were centrifuged and washed,and the suspension was taken,positive controls or actual samples were added and incubated with mesenchymal stem cell,then were incubated with protein L-PE solution.After the removal of the free protein L-PE,the mean fluorescence intensity of the PE was detected by flow cytometry.Results The method sensitivity is 115.54 ng·mL-1,far higher than the non-clinical research recommended sensitivity of 250-500 ng·mL-1.The precision of intra-assay and inter-assay were less than 20%.Assay cut points,low positive control concentration determination,sensitivity,precision and stability were validated in this study.Conclusion The method is proved to be sensitive,specific,rapid and suitable for the determination of anti-mesenchymal stem cell antibody in monkey serum and immunogenicity study.

ObjectiveTo investigate the therapeutic effect of the frozen and fresh preparations of human umbilical cord mesenchymal stem cells （hUC-MSC） on a rat model of liver cirrhosis after transplantation via the portal vein or the caudal vein. MethodsA total of 70 specific pathogen-free healthy male Sprague-Dawley rats were randomly divided into normal group （13 rats fed with ordinary tap water and rat food） and liver cirrhosis model group （57 rats given subcutaneous multi-point injection of mixed carbon tetrachloride/olive oil solution）. At week 8， the growth of rats was observed for both groups， and 3 rats were selected from each group for histopathological examination to confirm the formation of liver cirrhosis. A total of 50 rats were selected from the liver cirrhosis model and were divided into model group， portal vein group+fresh cell preparation group， portal vein+frozen cell preparation group， caudal vein+fresh cell preparation group， and caudal vein+frozen cell preparation group using a random number table， with 10 rats in each group. Fresh or frozen hUC-MSC were transplanted via the portal vein or the caudal vein， and after 4 weeks of administration， the different groups were compared in terms of the changes in liver function parameters and liver fibrosis degree. Continuous data were expressed as mean±standard deviation， and the independent-samples t test was used for comparison between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsAt week 8 of modeling， the model group showed the formation of pseudolobules of different sizes in the liver and met the diagnostic criteria for liver cirrhosis， with significant increases in the levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， total bilirubin （TBil）， and alkaline phosphatase （ALP） compared with the normal group （all P<0.001）， suggesting that the rat model of liver cirrhosis was established successfully. There were significant differences in the levels of ALT， AST， TBil， and ALP between the five groups （F=232.00， 177.10， 112.30， 121.70， all P<0.001）. Further comparison between two groups showed that the model group had significantly higher levels of ALT， AST， TBil， and ALP than the normal group （all P<0.01）， and the portal vein group+fresh cell preparation group， the portal vein+frozen cell preparation group， the caudal vein+fresh cell preparation group， and the caudal vein+frozen cell preparation group had significantly lower levels of ALT， AST， TBil， and ALP than the model group （all P<0.01）. ConclusionThere are significant improvements in liver function and liver fibrosis degree in a rat model of liver cirrhosis at week 4 after the transplantation of hUC-MSC， and frozen or fresh cell preparation and different transplantation approaches have no significant influence on treatment outcome.

Alismatis Rhizoma(AR)is widely used in Chinese medicine,and its major bioactive components,tri-terpenes,reportedly possess various pharmacological activities.Therefore,it is very important to study the metabolism of triterpenes in vivo.However,the metabolism of AR triterpene extract has not been comprehensively elucidated due to its complex chemical components and metabolic pathways.In this study,an ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry method,which was based on the characteristic ions from an established database of known triterpenes,was used to analyze the major metabolites in rats following the oral administration of Alismatis Rhizoma extracts(ARE).As a result,a total of 233 constituents,with 85 prototype compounds and 148 metabo-lites,were identified for the first time.Hydrogenation,oxidation,sulfate and glucuronidation conjugation were the major metabolic pathways for triterpenes in AR.In addition,the mutual in vivo transformation of known ARE triterpenes was discovered and confirmed for the first time.Those results provide comprehensive insights into the metabolism of AR in vivo,which will be useful for future studies on its pharmacodynamics and pharmacokinetics.Moreover,this established strategy may be useful in meta-bolic studies of similar compounds.

Objective:To explore the role and mechanism of long non-coding RNA KCNQ1 overlapping transcript 1 (LncRNA KCNQ1OT1) in the migration, proliferation and invasion of hepatocellular carcinoma (HCC).Methods:The experimental method was conducted. The expression levels of LncRNA KCNQ1OT1 in HCC tissues and normal liver tissues in the StarBase database were collected. The experimental methods including real-time quantitative PCR, cell transfection, scratch assay, CCK8 assay, Transwell assay, Western blot were used to determine the expression, migration, proliferation, invasion of LncRNA KCNQ1OT1 in HCC cells and its relationship with phosphatidylinositol 3-kinase/phosphorylated AKT Protein (PI3K /p-AKT) signaling pathways. Observation indicators: (1) expression of LncRNA KCNQ1OT1 in HCC tissues and normal liver tissues; (2) the migration of HepG2, SMCC-7721 and MHCC-97H HCC cells after LncRNA KCNQ1OT1 gene knockdown; (3) the proliferation and invasion of HepG2, SMCC-7721 and MHCC-97H HCC cells after LncRNA KCNQ1OT1 gene knockdown; (4) effects of LncRNA KCNQ1OT1 gene knockdown on PI3K/p-AKT signaling pathways. Measurement data with normal distribution were expressed as Mean± SD, and comparison between groups was analyzed using the t test. The Kaplan-Meier method was used to calculate survival rates and draw survival curves. Results:(1) Expression of LncRNA KCNQ1OT1 in HCC tissues and normal liver tissues. The expression levels of LncRNA KCNQ1OT1 in 374 HCC tissues and 50 normal liver tissues from StarBase database were 3.320±0.017 and 1.470±0.025, respectively, showing a significant difference ( t=5.24, P<0.05). Results of gene expression profile interactive analysis showed that the 30-month disease-free survival rates of HCC patients with high and low expression levels of LncRNA KCNQ1OT1 were 41% and 55%, respectively, with a significant difference ( χ2=6.209, P<0.05). The relative expression of LncRNA KCNQ1OT1 in HepG2, SMCC-7721and MHCC-97H cells were 1.470±0.042, 3.300±0.032, 4.040±0.031, respectively, versus 1.000±0.022 in normal liver cells (LO2), showing significant differences ( t=17.66, 95.40, 114.20, P<0.05). (2) The migration of HepG2, SMCC-7721 and MHCC-97H HCC cells after LncRNA KCNQ1OT1 gene knockdown. ① Results of cell transfection showed that the relative expression levels of LncRNA KCNQ1OT1 in HepG2, SMCC-7721 and MHCC-97H cells after LncRNA KCNQ1OT1 gene knockdown were 0.350±0.016, 0.310±0.020, 0.380±0.018, respectively, versus 1.000±0.021, 1.000±0.018, 1.000±0.019 in the negative control cells, showing significant differences ( t=23.40, 28.15, 22.32, P<0.05). ② Results of scratch assay showed that the healing rates of HepG2, SMCC-7721, MHCC-97H cells after LncRNA KCNQ1OT1 gene knockdown were 85.0%±1.9%, 75.0%±1.8%, 90.0%±1.7%, respectively, versus 100.0%±2.0%, 95.0%±1.8%, 72.0%±1.7% of the negative control cells, showing significant differences ( t=31.35, 47.36, 38.42, P<0.05). ③ Results of Transwell assay showed that the vertical migration rates of HepG2, SMCC-7721, MHCC-97H cells after LncRNA KCNQ1OT1 gene knockdown were 195±10, 205±12, 85±8, respectively, versus 520±11, 430±7, 405±20 of the negative control cells, showing significant differences between them ( t=922.30, 458.20, 708.40, P<0.05). (3) The proliferation and invasion of HepG2, SMCC-7721 and MHCC-97H HCC cells after LncRNA KCNQ1OT1 gene knockdown. ① Results of CCK8 assay showed that 72-hour optical densities of HepG2, SMCC-7721, MHCC-97H cells after LncRNA KCNQ1OT1 gene knockdown were 1.370±0.018, 1.240±0.016, 1.360±0.020, respectively, versus 0.900±0.023, 1.740±0.032, 1.230±0.025 of the negative control cells, with significant differences ( t=10.79, 12.00, 7.56, P<0.05). ② Results of Transwell assay showed that the invasion numbers of HepG2, SMCC-7721, MHCC-97H cells after LncRNA KCNQ1OT1 gene knockdown were 186±12, 155±7, 75±9, respectively, versus 505±1, 245±8, 300±15 of the negative control cells, showing significant differences ( t=955.90, 163.40, 530.90, P<0.05). (4) Effects of LncRNA KCNQ1OT1 gene knockdown on PI3K/p-AKT signaling pathways. Resluts of Western blot showed that the relative repression levels of PI3K in HepG2, SMCC-7721, MHCC-97H cells after LncRNA KCNQ1OT1 gene knockdown were 0.447±0.009, 0.430±0.012, 0.354±0.006, respectively, versus 0.820±0.017, 0.850±0.012, 0.531±0.001 of the negative control cells, showing significant differences ( t=18.94, 25.72, 27.46, P<0.05). The relative repression levels of p-AKT in HepG2, SMCC-7721, MHCC-97H cells after LncRNA KCNQ1OT1 gene knockdown were 0.343±0.015, 0.410±0.012, 0.579±0.006, respectively, versus 0.546±0.012, 0.620±0.012, 0.830±0.012 of the negative control cells, showing significant differences ( t=10.78, 12.86, 19.02, P<0.05). Conclusions:LncRNA KCNQ1OT1 plays an important role in the occurrence and development of HCC. LncRNA KCNQ1OT1 gene knockdown can inhibit the PI3K/AKT signaling pathways, so it can significantly inhibit the proliferation, migration and invasion of HCC cells.