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.

Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process. However, a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable. We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration. We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes, and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration. Furthermore, we identified a regeneration-induced cell (RIC) population in the epicardium-derived cells (EPDC), and demonstrated Angiopoietin 4 (Angpt4) as a specific regulator of heart regeneration. angpt4 expression is specifically and transiently activated in RIC, which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway, and further induces activation of cathepsin K in cardiomyocytes through RA signaling. Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation, while overexpression of angpt4 accelerates regeneration. Furthermore, we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes, and promote cardiac repair in mice after myocardial infarction, indicating that the function of Angpt4 is conserved in mammals. Our study provides a mechanistic understanding of heart regeneration at single-cell precision, identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration, and offers a novel therapeutic target for improved recovery after human heart injuries.
Humans ; Mice ; Rats ; Cell Proliferation ; Heart/physiology* ; Mammals ; Myocardial Infarction/metabolism* ; Myocytes, Cardiac/metabolism* ; Pericardium/metabolism* ; Single-Cell Analysis ; Zebrafish/metabolism*

【Objective】 To evaluate the safety and efficacy of balloon-expandable vertebral body stenting （VBS） in treating elderly patients with osteoporotic vertebral compression fractures. 【Methods】 Thirty-eight elderly patients with osteoporotic vertebral compression fractures were randomly divided into two groups according to the parity of their hospital admission numbers to receive VBS and traditional percutaneous kyphoplasty （PKP）， respectively. The two groups were compared regarding changes in the intensity of pain， functional score， imaging parameters related to vertebral compression， and sagittal Cobb angle as well as the incidence of bone cement leakage after treatment， to evaluate the safety and efficacy of VBS. 【Results】 All the patients underwent the operations smoothly， which were performed with the bilateral percutaneous puncture technique under local anesthesia by the same surgeon， and were followed up for more than half a year. Both VBS group and PKP group showed significant improvement in the visual analogue scale score， the Oswestry disability index， the height of the fractured vertebral body， and the Cobb angle at 3 days， 1 month， 3 months and 6 months after treatment （all P<0.05）. There were significant differences in those indicators between the two groups （all P<0.05）. 【Conclusion】 VBS is an effective treatment approach for elderly patients with osteoporotic vertebral compression fractures. It can effectively recover fractured vertebral body height， relieve patients’ pain， and have fewer complications such as bone cement leakage.

OBJECTIVE: To analyze the proliferation potential of bone marrow-derived mesenchymal stem cells (MSC) in patients with myelodysplastic syndrome (MDS). METHODS: The MSC derived from the 24 patients with newly diagnosed MDS (MDS-MSC group) and MSC derived from 15 patients with nutritional anemia (control group) in the Affiliated Hospital of Hebei University were used as the research objects. The proliferation potential of MSC was analyzed by colony-forming unit assay, doubling time, cumulative passaging, cell number after 10 days of culture with equal amount of MSC and MTT experiment. The mechanism of abnormal proliferation was analyzed by cell cycle experiment, apoptosis experiment and p21 gene expression assay. RESULTS: In the colony forming unit assay, the number of MDS-MSC colonies was 4.44±2.51, which was significantly lower than that of the control group (12.44±2.55)(P<0.01); the doubling time of MDS-MSC group was significantly longer than that of the control group (7.80±3.26 vs 3.63±0.85) (P<0.01); the number of MDS-MSC in 5×10 CONCLUSION The proliferative capability of MDS-MSC is significantly reduced, which relates with the arrest of cell cycle in G
Apoptosis ; Bone Marrow Cells ; Cell Proliferation ; Humans ; Mesenchymal Stem Cells ; Myelodysplastic Syndromes

E3 ubiquitin ligase TRIM21(tripartite motif containing 21) plays an important role in regulating cell biological functions and clinical prognosis as oncogene or tumor suppressor in different types of tumors. However,the biological functions and molecular mechanism of TRIM21 in hypopharyngeal squamous cell carcinoma (HPSCC) are still unclear.Our results showed that TRIM21 is highly expressed in moderately and well differentiated HPSCC, suggesting the role of TRIM21 in tumor differentiation. Overexpression and knockdown of TRIM21 inhibited or promoted cell proliferation and migration. Meanwhile, the expression of differentiation markers including KRT10 (keratin 10), IVL (involucrin) and TGM1 (transglutaminase 1) were increased and decreased upon TRIM21 overexpression or knockdown, respectively. The bioinformatics analysis of TRIM21 interacting protein identified by co-immunoprecipitation combined with mass spectrometry suggested that TRIM21 may be closely related to the regulation of cytoskeleton protein. We further demonstrated that TRIM21 interacted with KRT10. The inhibition of protein synthesis by cycloheximide led to upregulation of KRT10 in TRIM21 overexpressing FaDu cells, and ectopic expression of TRIM21 enhanced the ubiquitination level of KRT10. In summary, our results suggest that TRIM21 may promote the HPSCC differentiation by mediating ubiquitination of cytoskeleton proteins to improve the protein stability.

Objective: To investigate the effects of macrophage colony-stimulating factor (M-CSF) on the polarization and infiltration of M2 macrophages and the invasion and metastasis of tumor cells in ovarian cancer microenvironment. Methods: A co-culture system consisting of ovarian cancer cells (A2780 and SKOV3) and THP-1 derived macrophages was established in vitro. The M-CSF levels in culture medium and M-CSF mRNA levels in cancer cells and macrophages were detected by ELISA and qRT-PCR, respectively. The proportion of CD68+CD163+ M2 macrophages (polarization cells) was determined by flow cytometry. The invasive and metastatic ability of A2780 and SKOV3 cells after co-culturing with M2 macrophages were analyzed using Transwell assay. The expression levels of M-CSF, CD68+, CD163+ and E-cad in paraffin sections of 52 patients with ovarian cancer and 18 patients with benign ovarian tumor were detected by the immunohistochemistry staining, and their correlations and the relationship between M-CSF and clinicopathological features of ovarian cancer patients were analyzed. Results: The M-CSF levels in culture medium of the co-culture group (A2780 and SKOV3 cells co-cultured with M2 macrophages) were significantly higher than that of A2780 and SKOV3 cells alone (t=14.315 and 12.338, P＜0.01). Fluorescence quantitative PCR results showed that the increased M-CSF originated from the secretion of co-cultured ovarian cancer cells (t=29.915 and 36.826, P＜0.01). The proportions of CD68+CD163+ M2 macrophages in the A2780 cells co-cultured with M2 macrophages group and SKOV3 cells co-cultured with M2 macrophages group were (6.14±0.50)% and (7.32±0.67)%, respectively, which were significantly higher than that in the M2 macrophages alone group ([1.82±0.34]%, t=12.289 and 12.711, P＜0.01). Transwell assay showed that the co-culture environment enhanced the invasion of A2780 and SKOV3 cells (24.00±4.81 vs 75.20±6.42, t=11.058; 18.40±2.31 vs 61.60±9.66, t=7.537, P＜0.01). The expression levels of M-CSF in ovarian cancer tissues were positively correlated with the number of CD68+ cells and CD163+ cells (r=0.690 and 0.596, P＜0.01), and negatively with the expression levels of E-cad (r=-0.566, P＜0.01). Moreover, the expression levels of M-CSF and the number of CD68+ cells and CD163+ cells in ovarian cancer tissues were significantly higher than that in benign ovarian tumor tissues, however, the expression levels of E-cad were on the contrary. The expression levels of M-CSF in ovarian cancer tissues were significantly correlated with tumor stage, differentiation and lymphatic node metastasis (χ2=6.240, 6.612 and 4.544, respectively, P＜0.05). Conclusion The increased expression of M-CSF in ovarian cancer microenvironment may induce the polarization and infiltration of CD68+CD163+ M2 macrophages, and then promote the invasion and metastasis of ovarian cancer cells.

Objective: To understand the consistency of ALK Ventana-D5F3 immunohistochemistry (IHC) interpretation in Chinese lung adenocarcinoma among histopathologists from different hospitals, and to recommend solution for the problems found during the interpretation of ALK IHC in real world, with the aim of the precise selection of patients who can benefit from ALK targeted therapy. Methods: This was a multicenter and retrospective study. A total of 109 lung adenocarcinoma cases with ALK Ventana-D5F3 IHC staining were collected from 31 lung cancer centers in RATICAL research group from January to June in 2018. All cases were scanned into digital imaging with Ventana iSCANcoreo Digital Slide Scanning System and scored by 31 histopathologists from different centers according to ALK binary (positive or negative) interpretation based on its manufacturer′s protocol. The cases with high inconsistency rate were further analyzed using FISH/RT-PCR/NGS. Results: There were 49 ALK positive cases and 60 ALK negative cases, confirmed by re-evaluation by the specialist panel. Two cases (No. 2302 and No.2701) scored as positive by local hospitals were rescored as negative, and were confirmed to be negative by RT-PCR/FISH/NGS. The false interpretation rate of these two cases was 58.1% (18/31) and 48.4% (15/31), respectively. Six out of 31 (19.4%) pathologists got 100% accuracy. The minimum consistency between every two pathologists was 75.8%.At least one pathologist gave negative judgement (false negative) or positive judgement (false positive) in the 49 positive or 60 negative cases, accounted for 26.5% (13/49), 41.7% (25/60), respectively, with at least one uncertainty interpretation accounted for 31.2% (34/109). Conclusion There are certain heterogeneities and misclassifications in the real world interpretation of ALK-D5F3 IHC test, which need to be guided by the oncoming expert consensus based on the real world data.

OBJECTIVE: To investigate the phenotype and molecular mechanism of DCA on MDS cell model, and to study the response of chemotherapeutic medicines to MDS cells through multiple dimensions, such as cell proliferation, invasion, migration and apoptosis, thus revealing the molecular mechanism of DCA treatment of MDS and its relationship with SHP-1 gene methylation. METHODS: MTT assay was used to determine the survival rate of MDS cells after treated by different concentrations of DCA. The effect of DCA on the invasion and migration of MDS cells was detected by Transwell assay method. Apoplexin V-FITCPI was used to detect apoptosis, the MDS treatment on the mechanism of DCA was investigated by Western blot and Real-time PCR experiment. RESULTS: According to the experiment, it was found that tumor proliferation could be inhibited when MDS skm-1 cells was treated by DCA, and the absorbance was lower and the inhibitory effect was more obvious in the 2.0, 5.0 μmol/L DCA group than in the 0.5 μmol/L DCA group and the negative control group. Compared with the control group, the number of MDS skm-1 cells crossing through the transwell upper chamber was significantly decreased after DCA application. After treated with 0.5, 2.0 and 5.0 μmol/L DCA, the apoptosis rate of MDS cells was 4.54%, 9.31% and 16.58% respectively, while the apoptosis rate of the control group was 3.20%, which shows the apoptosis rate increased significantly with the concentration of DCA. After treatment of MDS cell lines with different concentration of DCA, the methylation status of SHP-1 gene was decreased with the increase of drug concentration, the expression of SHP-1 was increased, the expression of STAT3 was decreased and the level of phosphorylation was decreased. CONCLUSION By analyzing the phenotypic response of DCA treatment on MDS cells, it was found that interfere with MDS can be performed by inhibiting proliferation, metastasis, and inducing apoptosis in a dose-dependent way. It revealed that the molecular mechanism by DCA treatment can improve the methylation of SHP-1 gene and inhibit the expression of p-STAT3.
Apoptosis ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Decitabine ; Humans ; Protein Tyrosine Phosphatase, Non-Receptor Type 6

Myelodysplastic syndromes (MDS) comprise a group of malignant hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. The risk of transformation to acute myeloid leukemia (AML) is increasing. The initiating event in HSC of MDS leads to a growth advantage and subsequent clonal expansion, that is still poorly understood. Accumulating data indicate that the mesenchymal stem cells(MSCs) in MDS model display aberrant characteristics contributing to disease initiation and transformation into AML. MSC derived from MDS displayed the alteration in genetics, epigenetics and gene expression, which contribute to altered morphology, impaired proliferative and differentiation capacity and perturbed cytokine secretions, thus destroy in their ability to support normal hematopoiesis and contribute to malignant progression. A number of promising agents that target the interactions of the MDS clone with MSC are currently investigated in various phases of clinical trial, that might ultimately result in novel therapeutic strategies, targeting niche cells to attenuate leukemic progression. In this article, the current status of MDS treatment, the characteristics of MDS-MSC senescence and phenotypes, the changes of hematopoietic function sapported by senescent MDS-MSC, the significane of MDS-MSC in MDS prognosis and the MDS-MSC as potential target for treatment of MDS are summarized.
Hematopoiesis ; Hematopoietic Stem Cells ; Humans ; Leukemia, Myeloid, Acute ; Mesenchymal Stem Cells ; Myelodysplastic Syndromes

PURPOSE: Insufficient sensitivity and specificity prevent the use of most existing biomarkers for early detection of breast cancer. Recently, it was reported that serum microRNAs (miRNAs) may be potential biomarkers in many cancer diseases. In this study, we investigated whether serum levels of 5 miRNAs including miR-21, miR-125b, miR-145, miR-155, and miR-365 could discriminate breast cancer patients and healthy controls. METHODS: Serum levels of miRNAs were measured by using quantitative real-time polymerase chain reaction in 99 breast cancer patients and 21 healthy controls. The abundance change of serum miRNAs were also evaluated following surgical resection in 20 breast cancer patients. Receiver operating characteristic (ROC) curve analysis was performed to assess the sensitivity and specificity of miRNAs as diagnostic biomarkers. RESULTS: Serum levels of miR-21 and miR-155 was significantly higher, while miR-365 was significantly lower in breast cancer as compared with healthy controls. The serum levels of miR-21 and miR-155 significantly decreased following surgical resection. Additionally, the serum level of miR-155 at stages I and II was significantly higher compared to stage III. The serum miR-145 level was remarkably higher in progesterone receptor (PR)-positive patients than PR-negative. The positivity of miR-21, miR-155, and miR-365 was high compared to CA 153 and CEA in breast cancer. ROC curve analyses of a combination of miR-21, miR-155, and miR-365 yielded much higher area under curve and enhanced sensitivity and specificity in comparison to each miRNA alone. CONCLUSION: The combination of serum miR-21/miR-155/miR-365 may potentially serve as a sensitive and specific biomarker that enables differentiation of breast cancer from healthy controls.
Area Under Curve ; Biomarkers ; Breast Neoplasms* ; Breast* ; Humans ; MicroRNAs ; Real-Time Polymerase Chain Reaction ; Receptors, Progesterone ; ROC Curve ; Sensitivity and Specificity