This study adopted the policy text analysis method,review the historical background of the enactment,aimed to comparatively analyze the international pharmaceutical trade policies of the BRICS countries.The main objectives of the BRICS countries'international pharmaceutical trade policies included ensuring stable and accessible drug supply,expanding exports of domestic products and creating a favorable political environment.For these purposes,Brazil,Russia,and South Africa all ensure drug supply through substantial imports.However,they have also taken measures such as compulsory patent licensing and promoting localization of production by foreign companies to reduce import dependence.India,on the other hand,protects its domestic industry by resisting drug imports to ensure drug supply while simultaneously promoting the export of pharmaceutical products.China continually optimizes approval and data monitoring procedures to align with international standards,creating a favorable trade environment and expanding exports.China should further refine its international pharmaceutical trade policies while ensuring the autonomy of domestic drug research and supply,fostering stronger collaboration within BRICS nations and promoting global access to public healthcare products.

Objective:To investigate the effects of PD-1 monoclonal antibody therapy on the peripheral and local immune microenvironment of patients with microsatellite instability-high(MSI-H)rectal cancer.Methods:Samples of peripheral blood and tumor biopsy were collected from a patient with MSI-H rectal cancer before and after PD-1 monoclonal antibody treatment.The samples were dissociated into single-cell suspensions using a combination of enzymatic and mechanical methods.Immune-related marker expression on peripheral and tumor-infiltrating im-mune cells was analyzed using single-cell mass cytometry(CyTOF).Results:According to the results of CyTOF analysis,CD45+immune cells in the peripheral blood and tumor tissues were categorized into 39 and 34 cell subsets,respectively,before and after PD-1 monoclonal antibody treatment(the correlation is unclear and ambiguous).After PD-1 monoclonal antibody treatment,differences were observed in the relative abundance of immune cell subsets:B cells significantly decreased in the peripheral blood,while B cells and γδT cells significantly increased in the tumor tissue;neutrophils significantly decreased,and the proportion of CD4+TEM cells in T cell subsets significantly increased,whereas CD4+Treg cells significantly decreased.Additionally,there were differences in the expression of immune-related markers in multiple immune cell subsets in both peripheral blood and tumor tissues,with CCR6 showing a significant increase in expression across all subsets,while ICOS and PD-1 expressions in T cell subsets were significantly reduced(the specific tissues for these cells or factors are unclear).Conclusion:After PD-1 monoclonal antibody treatment in MSI-H rectal cancer,changes occurred in the composition of immune cells and the expression of immune-related markers in both peripheral blood and tumor tissues.This study reveals the dynamic adjustment of the immune microenvironment and provides important evidence for understanding the therapeutic mechanism of PD-1 monoclonal antibodies.

ObjectiveTo investigate the effect of Yiqi Tongxin formula （YQTM） on liver inflammation in apolipoprotein E^-∕- （ApoE^-∕-） mice by regulating the nuclear transcription factor-κB （NF-κB）/NOD-like receptor protein 3 （NLRP3） signaling pathway. MethodForty ApoE^-∕- mice were randomly divided into a model group， an atorvastatin group （positive drug group）， and low-， medium-， and high-dose YQTM groups （0.39， 0.78， 1.56 g·kg^-1）. Each drug administration group was given the corresponding concentration of the drug by gavage on the basis of high-fat feeding for 12 consecutive weeks. Eight C57BL/6J mice were used as a blank group and fed with normal chow. After 12 weeks， oil red O staining and Masson staining were used to observe the aortic lesions in mice and to determine whether the modeling was successful. Oil red O staining was used to observe the lipidosis in the livers of mice. Hematoxylin-eosin （HE） staining was used to observe the tissue lesions in the livers of mice. Masson staining was used to observe the distribution of collagen fibers in the livers of mice. Enzyme markers were used to detect the total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL-C）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT） in mouse serum， as well as total cholesterol （TC） and triglyceride （TG） in the liver. Interleukin-1β （IL-1β） and IL-18 were detected in mouse liver by enzyme-linked immunosorbent assay （ELISA）. Immunohistochemistry （IHC） was utilized to observe the expression regions of NF-κB and NLRP3 in the livers of mice. Western blot was employed to detect the protein expression levels of NF-κB， NF-κB inhibitory protein （IκB）， IκB kinase β （IKKβ）， phosphorylated NF-κB （p-NF-κB）， phosphorylated IκB （p-IκB）， phosphorylated IKK β （p-IKKβ）， NLRP3， and Caspase-1 in the livers of mice. ResultCompared with the blank group， the model group showed severe aortic lipidosis， and the intracellular fat droplets in the livers aggregated in large quantities. The cytoplasm was filled with fat vacuoles（P<0.01）. The serum levels of TG， TC， LDL-C， AST， and ALT were significantly elevated in the mice（P<0.01）. TG and TC levels were elevated in the liver（P<0.01）. The levels of IL-1β and IL-18 in liver tissue， as well as the protein expression levels of NF-κB， IκB， IKKβ， p-NF-κB， p-IκB， p-IKKβ， NLRP3， and Caspase-1 in the liver were significantly elevated（P<0.01）. Compared with the model group， the aortic arch plaques of mice in each YQTM group were attenuated， and the fat aggregation in the liver was reduced. The inflammatory cell infiltration was alleviated（P<0.05，P<0.01）. The serum levels of TG， TC， LDL-C， AST， and ALT were significantly reduced（P<0.05，P<0.01）. TG and TC levels in the liver were reduced. The IL-1β and IL-18 levels in liver tissue， as well as protein expression levels of NF-κB， IκB， IKKβ， p-NF-κB， p-IκB， p-IKKβ， NLRP3， and Caspase-1 in the liver were significantly reduced（P<0.05，P<0.01）. ConclusionThe intervention mechanism of YQTM on liver inflammation in ApoE^-∕- mice may be related to the down-regulation of the NF-κB/NLRP3 signaling pathway.

Based on the strategy of metabolomics combined with bioinformatics, this study analyzed the potential allergens and mechanism of pseudo-allergic reactions (PARs) induced by the combined use of Reduning injection and penicillin G injection. All animal experiments and welfare are in accordance with the requirements of the First Affiliated Experimental Animal Ethics and Animal Welfare Committee of Henan University of Chinese Medicine (approval number: YFYDW2020002). Based on UPLC-Q-TOF/MS technology combined with UNIFI software, a total of 21 compounds were identified in Reduning and penicillin G mixed injection. Based on molecular docking technology, 10 potential allergens with strong binding activity to MrgprX2 agonist sites were further screened. Metabolomics analysis using UPLC-Q-TOF/MS technology revealed that 34 differential metabolites such as arachidonic acid, phosphatidylcholine, phosphatidylserine, prostaglandins, and leukotrienes were endogenous differential metabolites of PARs caused by combined use of Reduning injection and penicillin G injection. Through the analysis of the "potential allergen-target-endogenous differential metabolite" interaction network, the chlorogenic acids (such as chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, and isochlorogenic acid A) and β-lactam allergens in the combination of the two may be mainly regulated by PLD1, PLA2G12A and CYP1A1. The three upstream signal target proteins mainly activate the arachidonic acid metabolic pathway, promote the degranulation of mast cells, release downstream endogenous inflammatory mediators, and induce PARs.

OBJECTIVE To investigate the effects of Yiqi tongmai formula on atherosclerosis （AS） in ApoE－/－ mice and its mechanism. METHODS Forty ApoE－/－ mice were randomly divided into model group， positive control group [atorvastatin calcium， 2.6 mg/（kg·d）]， and low-dose， medium-dose and high-dose groups of Yiqi tongmai formula [0.46， 0.91， 1.82 g/（kg·d）， by raw material]， with 8 mice in each group. Eight C57BL/6J mice were selected as the normal group. Except for the normal group， the other groups were given a high-lipid diet and relevant drug or normal saline intragastrically， once a day， for 12 consecutive weeks. After the last medication， the serum levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C） and high-density lipoprotein cholesterol （HDL-C） as well as the contents of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β） and monocyte chemoattractant protein-1 （MCP-1） were measured in mice. The proportion of aortic plaque area in each group of mice was detected and calculated， and the pathological morphological changes of the aortic sinus were observed； the protein phosphorylation levels of aortic phosphoinositide 3-kinase （PI3K）， protein kinase B （aka Akt） and mammalian target of rapamycin （mTOR） were examined. RESULTS Compared with the model group， the serum levels of TC， TG and LDL-C and the contents of TNF-α， IL-1β and MCP-1 （including low-dose group） were decreased significantly in medium-dose and high-dose groups of Yiqi tongmai formula， while the content of HDL-C in high-dose group was increased significantly （P＜0.05 or P＜0.01）； aortic plaques of the mice were reduced in Yiqi tongmai formula groups to different extents， and pathological changes such as lipid deposition and inflammatory cell infiltration were relieved to different extents； the proportion of aortic plaque area， the protein phosphorylation levels of PI3K， Akt and mTOR in aortic tissue were significantly reduced in medium-dose and high-dose groups of Yiqi tongmai formula （P＜0.05 or P＜0.01）. CONCLUSIONS Yiqi tongmai formula can improve lipid metabolism， reduce inflammatory response， and delay plaque development in AS mice. Its effect may be related to the inhibition of PI3K/Akt/mTOR signaling pathway activation.

Malignant tumor is a major disease affecting human health. The nano-delivery system itself has a unique size effect and it can achieve tumor-targeted distribution of drug molecules, improve the therapeutic effect, and reduce the toxic and side effects on normal tissues and cells after functional modification. Patient-derived xenografts (PDX) models can be established by transplanting patient-derived cancer cells or small tumor tissue into immunodeficient mice directly. Compared with the tumor cell line model, this model can preserve the key features of the primary tumor such as histomorphology, heterogeneity, and genetic abnormalities, and keep them stable between generations. PDX models are widely used in drug evaluation, target discovery and biomarker development, especially providing a reliable research platform for the diagnosis and treatment evaluation of nano-delivery systems. This review summarizes the application of several common cancer PDX models in the evaluation of nano-delivery systems, in order to provide references for researchers to perform related research.

OBJECTIVE: To investigate the efficacy and safety of daratumumab in treatment of multiple myeloma (MM) patients with renal impairment (RI). METHODS: The clinical data of 15 MM patients with RI who received daratumumab-based regimen from January 2021 to March 2022 in three centers were retrospectively analyzed. Patients were treated with daratumumab or daratumumab combined with dexamethasone or daratumumab combined with bortezomib and dexamethasone and the curative effect and survival were analyzed. RESULTS: The median age of 15 patients was 64 (ranged 54-82) years old. Six patients were IgG-MM, 2 were IgA-MM,1 was IgD-MM and 6 were light chain MM. Median estinated glomerular filtration rate (eGFR) was 22.48 ml/(min·1.73 M₂). Overall response rate of 11 patients with MM was 91% (≥MR), including 1 case of stringent complete response (sCR), 2 cases of very good partial response (VGPR), 3 cases of partial response (PR) and 4 cases of minor response (MR). The rate of renal response was 60%(9/15), including 4 cases of complete response (CR), 1 case of PR and 4 cases of MR. A median time of optimal renal response was 21 (ranged 7-56) days. With a median follow-up of 3 months, the median progression-free survival and overall survival of all patients were not reached. After treatment with daratumumab-based regimen, grade 1-2 neutropenia was the most common hematological adverse reaction. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections. CONCLUSION Daratumumab-based regimens have good short-term efficacy and safety in the treatment of multiple myeloma patients with renal impairment.
Humans ; Middle Aged ; Aged ; Aged, 80 and over ; Multiple Myeloma/drug therapy* ; Retrospective Studies ; Dexamethasone/therapeutic use* ; Antibodies, Monoclonal/therapeutic use* ; Bortezomib/therapeutic use* ; Renal Insufficiency/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*

ObjectiveTo explore the association between daily executive function and core symptoms， the symptoms of attention deficit hyperactivity disorder （ADHD） in children with autism spectrum disorder （ASD）， and the moderating effect of theory of mind and other cognitive abilities on this association. MethodsChildren aged 6-12 years with ASD were recruited， and 86 children were identified according to the inclusion and exclusion criteria. Wechsler Intelligence Test for Children， Fourth Edition （WISC-Ⅳ）， Strange Story Test （SST） and Behavior Rating Inventory of Executive Function （BRIEF） were used to evaluate children's cognitive ability. Swanson Nolan and Pelham-Version Ⅳ Scale （SNAP-Ⅳ）， Social Responsiveness Scale （SRS）， and Repetitive Behavior Scale-Revise （RBS-R） were used to assess the severity of ADHD symptoms， social impairment， and repetitive stereotyped behavior. Multiple linear regression was used to explore the association between daily executive function and ADHD symptoms， social impairment， repetitive stereotyped behaviors. ResultsAfter controlling for the score of strange stories， verbal comprehension index （VCI） and other factors， the full scale score and each index of BRIEF were positively correlated with full scale score of SNAP （b = 0.619-0.741， b’ = 0.637-0.755）， SRS （b = 0.928-1.200， b’ = 0.417-0.513） and RBS-R （b = 0.326-0.525， b’ = 0.339-0.520） in children with ASD （P< 0.05）， and the SNAP total score was more strongly correlated with the full scale BRIEF score and each index score （b’ = 0.637-0.755，P< 0.01）. In addition to daily executive function， strange stories score （b = -2.218- -1.839） and age （b = 3.181-4.037） were also the important factors affecting the social function of children with ASD （P< 0.01）. There were no moderating effects of strange stories score and age on the association between BRIEF score and full scale score of SNAP， SRS， and RBS-R（P> 0.05）. ConclusionThe deficits of daily executive function in school-aged ASD children are significantly associated with core symptoms and ADHD symptoms， and the association is independent of other cognitive domains， such as theory of mind and verbal comprehension intelligence quotient.

Objective:To compare the clinical effects of acute shortening-lengthening technique with antibiotic calcium sulfate-loaded bone transport technique for the treatment of segmental tibial defects after trauma.Methods:The clinical data of 58 patients with large tibial defects treated by Ilizarov technique in Xi′an Honghui Hospital Affiliated to Xi′an Jiaotong University from May 2014 to December 2019 were retrospectively analyzed. Thirty patients were treated by acute shortening-lengthening (group A), and they were divided into those who were successful in one-time shortening during operation (group A1) and those who needed gradual shortening after operation (group A2) according to different shortening conditions. And 28 patients by antibiotic calcium sulfate-loaded bone transport (group B). The external fixation time (EFT) and external fixation index (EFI) of the two groups were compared. Bone defect healing and limb functions were evaluated according to the Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria. Complications were compared by Paley classification. The measurement data of normal distribution were expressed as ± s, and t-test was used for comparison between groups; the count data were expressed as n(%), and the chi-square test, Fisher exact probability method or Mann-Whitney U test were used for comparison between groups. Results:Patients were followed for(27.5±5.1)months. There was no significant difference in EFT, EFI, bone defect healing and limb functions between the two groups( P>0.05). The incidence of Grade-Ⅱ[41.2% (7/17)], Grade-Ⅲ [47.1% (8/17)] pin-tract infection in group A1 and Grade-Ⅱ[46.2% (6/13)], Grade-Ⅲ pin-tract [53.8% (7/13)] in group A2 was significantly higher than those in group B[14.3% (4/28)], [17.9% (5/28)] ( P<0.05). The number of complications per capita in group A1 [(1.4±0.3) times/case] and in group A2 [(1.5±0.3) times/case]was significantly higher than that in group B [(1.1±0.5) times/case]. Conclusions:Patients can be cured successfully by both acute shortening-lengthening and bone transport techniques. Compared with acute shortening-lengthening group, the complication incidence in antibiotic calcium sulfate-loaded bone transport group was lower, especially, the infection-related complications. Therefore, antibiotic calcium sulfate-loaded bone transport technique has a greater application prospect in patients with large segmental bone defects caused by infection or osteomyelitis.

Objective:To analyze the therapeutic effect of sural neurocutaneous flap combined with antibiotic-impregnated calcium sulfate and autogenous iliac bone graft of chronic calcaneal osteomyelitis.Methods:A retrospective analysis was peformed in 29 patients with chronic calcaneal osteomyelitis treated with sural neurocutaneous flap combined with antibiotic-impregnated calcium sulfate and autogenous iliac bone graft in the Xi′an Honghui Hospital Affiliated to Xi′an Jiaotong University from April 2013 to January 2020. There were 19 males and 10 females, with the age of (45.38±12.85) years, ranged from 22 to 67 years. The course of disease was (16.00±6.96) months, ranged from 6 to 36 months. The skin defect area was (41.9±15.9) cm 2, ranged from 11.8 to 86.8 cm 2. The causes of injury: 18 cases of high fall, 6 cases of traffic accidents, 3 cases of heavy rolling, the remaining 2 cases were machine strangulation and sharp stab wounds. The inflammatory markers [white blood cell (WBC), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), C reactive protein (CRP)] and bone healing time were recorded before operation, 2, 4, 8 weeks and 6 months after operation. During the follow-up period, the flap texture, survival were observed, and the ankle-posterior foot function recovery was evaluated by the American Association of Foot and Ankle Surgery (AOFAS) score were observed before and after the operation, and the incidence of complications were recorded. The measurement data were expressed as mean±standard deviation ( ± s), and the t-test was used for inter-group comparison; the levels of WBC, ESR, PCT and CRP at different time points before and after operation were compared by repeated measurement ANOVA, and the LSD t-test was used for pairwise comparison. Results:All the 29 patients were followed up for (14.51±6.10) months, ranged from 6 to 30 months. All the flaps survived without abrasion, ulceration, or skin protrusion, and all patients could walk normally with shoes. There were 28 cases of stage I bone healing, with an average of (5.87±2.07) months, ranged from 3 to 12 months. The inflammatory indexes was significantly decreased at different time points after operation ( P<0.05). There was no significant difference between 6 months and 8 weeks after operation ( P>0.05), while there was significant difference at other time points ( P<0.05). The ankle-posterior foot score of AOFAS at 6 months after treatment was significantly higher than that before treatment (83.44±7.93 vs 55.37±8.07), the differences was statistically significant ( P<0.05). The clinical efficacy of foot function recovery was excellent in 12 cases, good in 15 cases and fair in 2 cases among 29 patients .The excellent and good rate was 93.1% (27/29). One patient recurred 1 month after operation and was re-implanted with antibiotic-loaded calcium sulfate mixed autogenous iliac bone after debridement, no recurrence was found. The total complication rate was 31.0%, but there was no significant impact on the patient's life in the later period. All patients returned to daily life and work. Conclusion:The treatment of chronic calcaneal osteomyelitis with sural neurocutaneous flap combined with antibiotic-impregnated calcium sulfate and autogenous iliac bone graft can effectively control infection, reconstruct calcaneal and soft tissue structure, promote functional recovery of affected limb, and ultimately improve the patient′s quality of life.