OBJECTIVE To investigate the targeting effect of folic acid-modified crebanine nanoparticles （FA-Cre@PEG- PLGA NPs， hereinafter referred to as “NPs”） combined with ultrasound irradiation on M109 cells in vitro and in vivo after administration， and explore the anti-tumor mechanism. METHODS CCK-8 assay was used to detect the inhibitory effect of NPs combined with ultrasound irradiation on the proliferation of M109 cells， and the best ultrasound time was selected. Using human lung cancer A549 cells as a control， the targeting of NPs combined with ultrasound irradiation to M109 cells was evaluated by free folic acid blocking assay and cell uptake assay. The effects of NPs combined with ultrasound irradiation on the migration， invasion， apoptosis， cell cycle and reactive oxygen species （ROS） levels of M109 cells were detected by cell scratch test， Transwell chamber test and flow cytometry at 1 h after 958401536@qq.com administration； the changes of mitochondrial membrane potential （MMP） were observed by fluorescence inverted microscope. A mouse subcutaneous tumor model of M109 cells was constructed， and the in vivo tumor targeting of NPs combined with ultrasound irradiation was investigated by small animal in vivo imaging technology. RESULTS NPs combined with ultrasound irradiation could significantly inhibit the proliferation of M109 cells， and the optimal ultrasound time was 1 h after administration. The free folic acid could antagonize the inhibitory effect of NPs on the proliferation of M109 cells， and combined with ultrasound irradiation could partially reverse this antagonism. Compared with A549 cells， the uptake rate of NPs in M109 cells was significantly higher （P＜0.01）， and ultrasound irradiation could promote cellular uptake. NPs combined with ultrasound irradiation could inhibit the migration and invasion of M109 cells and block the cell cycle in the G0/G1 and G2/M phases. Compared with control group， the apoptosis rate of M109 cells and ROS level were increased significantly （P＜0.01）， while the MMP decreased significantly （P＜0.01） in the different concentration （100， 200， 300 μg/mL） groups of M109 cells. Compared with the mice in non-ultrasound group， the fluorescence intensity and tumor-targeting index of the tumor site in the 0 h ultrasound group were significantly enhanced （P＜0.05 or P＜0.01）. CONCLUSIONS NPs combined with ultrasound irradiation have a strong targeting effect on M109 cells in vitro and in vivo， the anti-tumor mechanism includes inhibiting cell migration and invasion， blocking cell cycle， and inducing apoptosis.

OBJECTIVE: To investigate the impact of different iterative cone beam CT (iCBCT) scanning beam currents from a ring-mounted linac on synthetic CT image quality for lung adaptive radiotherapy under lung scanning protocol. METHODS: The CIRS lung motion phantom was configured to simulate conventional respiratory motion pattern, followed by 4D-CT simulation. After transferring the radiotherapy plan to the ring-mounted Halcyon 3.0 linac, three groups of typical iCBCT scans with different beam currents [ I _low (160 mA), I _middle (282 mA), and I _high (491 mA)] were performed and corresponding image reconstructions were completed. Synthetic CT (sCT) images were subsequently obtained based on the deformable registration algorithm. RESULTS: Compared to the corresponding CBCT images, the sCT images exhibited a significant reduction in artifacts. The fine structure of the planning CT (pCT) image was preserved for sCT images corresponding to different scanning beam currents, with Dice similarity coefficients exceeding 0.90 for all cases. CONCLUSION The image quality of sCT corresponding to different iCBCTs is comparable to that of pCT, and changes in iCBCT beam parameters have a negligible impact on sCT image quality. Taking into account both image quality and imaging dose factors associated with the beam currents, iCBCT with a lower beam current on the ring-mounted Halcyon linac offers greater clinical value in lung adaptive radiotherapy.
Cone-Beam Computed Tomography/methods* ; Phantoms, Imaging ; Humans ; Radiotherapy Planning, Computer-Assisted/methods* ; Lung/diagnostic imaging* ; Lung Neoplasms/diagnostic imaging*

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

ObjectiveTo investigate the role of mature-tRNA-Asp-GTC and pre-tRNA-Arg-TCT in the ferroptosis phenotype of ovarian cancer （OC） cells and the regulatory mechanism of gypenoside L （Gyp-L） on mature-tRNA-Asp-GTC and pre-tRNA-Arg-TCT in OC cells. MethodsThe proliferation of human ovarian adenocarcinoma OVCAR3 cells was detected by cell counting kit-8 （CCK-8） assay， and the half-maximal inhibitory concentration （IC₅₀） values of cisplatin （DDP）， Gyp-L， and DDP in the presence of Gyp-L were calculated to determine the intervention concentration for subsequent experiments. Cell cloning assay and scratch assay reflected the proliferation and migration ability of OVCAR3 cells. PANDORA-seq small RNA sequencing was used to detect the differentially expressed transfer RNA-derived small RNAs （tsRNAs） in the cells after Gyp-L intervention， and the corresponding target genes of the tsRNAs were found by the RNAhybrid software. Malondialdehyde （MDA）， glutathione （GSH）， and lipid peroxide （LPO） levels were measured by colorimetry or enzyme linked immunosorbent assay （ELISA） method， Fe²⁺ content by FerroOrange fluorescent probe， and reactive oxygen species （ROS） content by DCFH-DA fluorescent probe to reflect the occurrence of ferroptosis in OVCAR3 cells. OVCAR3 cells were divided into a control group， a 50 µmol·L^-1 Gyp-L group， and a 100 µmol·L^-1 Gyp-L group. Quantitative real-time polymerase chain reaction （PCR） was performed to detect the expression of mature-tRNA-Asp-GTC， mature-tRNA-Leu-CAA， mature-mt_tRNA-Tyr-GTA_5_end， mature-tRNA-Val-CAC， mature-mt_tRNA-Glu-TTC， pre-tRNA-Arg-TCT， mature-tRNA-Asn-GTT， hydroxymethylbilane synthase （HMBS）， Wnt， β-catenin， glutathione peroxidase 4 （GPX4）， Kelch-like ECH-associated protein 1 （KEAP1）， nuclear factor erythroid 2-related factor 2 （Nrf2）， activating transcription factor 3 （ATF3）， cystine/glutamate antiporter xCT， lysophosphatidylcholine acyltransferase 3 （LPCAT3）， and arachidonate 15-lipoxygenase （ALOX15）. Western blot was performed to detect the expression of HMBS， Wnt， β-catenin， GPX4， KEAP1， Nrf2， ATF3， xCT， LPCAT3， and ALOX15 proteins. ResultsThe 50 µmol·L^-1 Gyp-L， 100 µmol·L^-1 Gyp-L， DDP， 50 µmol·L^-1 Gyp-L+DDP， and 100 µmol·L^-1 Gyp-L+DDP groups showed significantly inhibited proliferation and migration of OVCAR3 cells （P<0.05） and exacerbated cell ferroptosis as reflected by the increase in the content of ROS， MDA， LPO， and Fe²⁺， as well as a decrease in the content of GSH （P<0.05）. Compared with the control group， Gyp-L effectively interfered with the expression of 25 tsRNAs in OVCAR3 cells （P<0.05， |log₂Fc|>1）. Pre-tRNA-Arg-TCT/HMBS/Wnt/β-catenin/GPX4， pre-tRNA-Arg-TCT/KEAP1/NRF2/xCT， mature-tRNA-Asp-GTC/ATF3/KEAP1/NRF2/xCT， and mature-tRNA-Asp-GTC/LPCAT3/ALOX15 axial expression was significantly aberrant after Gyp-L intervention （P<0.05）. ConclusionThe pre-tRNA-Arg-TCT/HMBS/Wnt/β-catenin/GPX4， pre-tRNA-Arg-TCT/KEAP1/Nrf2/xCT， mature-tRNA-Asp-GTC/ATF3/KEAP1/Nrf2/xCT， and mature-tRNA-Asp-GTC/LPCAT3/ALOX15 signaling pathways are involved in OC development. Gyp-L inhibits OC development by activating OVCAR3 cell ferroptosis onset mainly through the mature-tRNA-Asp-GTC/ATF3/KEAP1/Nrf2/xCT and mature-tRNA-Asp-GTC/LPCAT3/ALOX15 signaling axes.

ObjectiveWith the epidermal growth factor receptor（EGFR）/Signal Transducers and Activators of Transcription（STAT3）/Hexokinase 2（HK2） signaling pathway in atherosclerosis （AS） and ovarian cancer （OC） as the entry point， this paper discusses the molecular mechanism of Gypenoside L （Gyp-L） treating AS and OC with different diseases， provides a new perspective and theoretical basis for TCM treating AS and OC with EGFR-STAT3-HK2 pathway， and enriches the scientific connotation of the theory of "cytoskeleton in the heart". MethodsCCK-8 was used to detect the proliferation of HUVEC and OVCAR-3 cells， in order to determine the intervention concentration for subsequent experiments. The colorimetric method was used to detect the NO content in HUVEC and the contents of pyruvate and LDH in two cell lines. Cell cloning experiments and scratch experiments reflect the proliferation and migration ability of OVCAR-3 cells. Western blot was used to detect the expression levels of relevant proteins. Furthermore， two cell models overexpressing EGFR were constructed and co treated with Gyp-L. HUVEC cells were divided into control， ox-LDL， OE-NC， OE-EGFR， OE-NC+Gyp-L， and OE-EGFR+Gyp-L group. OVCAR-3 cells were divided into control， OE-NC， OE-EGFR ， OE-NC+Gyp-L， and OE-EGFR+Gyp-L group. The colorimetric method was used to detect the NO content in HUVEC and the contents of pyruvate and LDH in two cell lines. Western blot was used to detect the expression levels of EGFR-STAT3-HK2 pathway related proteins. Cell cloning experiments and scratch experiments reflect the proliferation and migration ability of OVCAR-3 cells. ResultsGyp-L can significantly reduce the NO content of HUVEC and the pyruvate and LDH content of two cell lines （P<0.05）； Inhibit the proliferation and migration ability of OVCAR-3 cells； Reduce the expression levels of EGFR/STAT3/HK2 pathway related proteins in HUVEC and OVCAR-3 cell lines （P<0.05）， and inhibit the glycolysis pathway. ConclusionGyp-L can inhibit glycolysis in HUVEC and OVCAR-3 cells through the EGFR/STAT3/HK2 pathway，thereby suppressing the occurrence and development of AS and OC.

ObjectiveTo investigate the role of mature-tRNA-Asp-GTC and pre-tRNA-Arg-TCT in the ferroptosis phenotype of ovarian cancer （OC） cells and the regulatory mechanism of gypenoside L （Gyp-L） on mature-tRNA-Asp-GTC and pre-tRNA-Arg-TCT in OC cells. MethodsThe proliferation of human ovarian adenocarcinoma OVCAR3 cells was detected by cell counting kit-8 （CCK-8） assay， and the half-maximal inhibitory concentration （IC₅₀） values of cisplatin （DDP）， Gyp-L， and DDP in the presence of Gyp-L were calculated to determine the intervention concentration for subsequent experiments. Cell cloning assay and scratch assay reflected the proliferation and migration ability of OVCAR3 cells. PANDORA-seq small RNA sequencing was used to detect the differentially expressed transfer RNA-derived small RNAs （tsRNAs） in the cells after Gyp-L intervention， and the corresponding target genes of the tsRNAs were found by the RNAhybrid software. Malondialdehyde （MDA）， glutathione （GSH）， and lipid peroxide （LPO） levels were measured by colorimetry or enzyme linked immunosorbent assay （ELISA） method， Fe²⁺ content by FerroOrange fluorescent probe， and reactive oxygen species （ROS） content by DCFH-DA fluorescent probe to reflect the occurrence of ferroptosis in OVCAR3 cells. OVCAR3 cells were divided into a control group， a 50 µmol·L^-1 Gyp-L group， and a 100 µmol·L^-1 Gyp-L group. Quantitative real-time polymerase chain reaction （PCR） was performed to detect the expression of mature-tRNA-Asp-GTC， mature-tRNA-Leu-CAA， mature-mt_tRNA-Tyr-GTA_5_end， mature-tRNA-Val-CAC， mature-mt_tRNA-Glu-TTC， pre-tRNA-Arg-TCT， mature-tRNA-Asn-GTT， hydroxymethylbilane synthase （HMBS）， Wnt， β-catenin， glutathione peroxidase 4 （GPX4）， Kelch-like ECH-associated protein 1 （KEAP1）， nuclear factor erythroid 2-related factor 2 （Nrf2）， activating transcription factor 3 （ATF3）， cystine/glutamate antiporter xCT， lysophosphatidylcholine acyltransferase 3 （LPCAT3）， and arachidonate 15-lipoxygenase （ALOX15）. Western blot was performed to detect the expression of HMBS， Wnt， β-catenin， GPX4， KEAP1， Nrf2， ATF3， xCT， LPCAT3， and ALOX15 proteins. ResultsThe 50 µmol·L^-1 Gyp-L， 100 µmol·L^-1 Gyp-L， DDP， 50 µmol·L^-1 Gyp-L+DDP， and 100 µmol·L^-1 Gyp-L+DDP groups showed significantly inhibited proliferation and migration of OVCAR3 cells （P<0.05） and exacerbated cell ferroptosis as reflected by the increase in the content of ROS， MDA， LPO， and Fe²⁺， as well as a decrease in the content of GSH （P<0.05）. Compared with the control group， Gyp-L effectively interfered with the expression of 25 tsRNAs in OVCAR3 cells （P<0.05， |log₂Fc|>1）. Pre-tRNA-Arg-TCT/HMBS/Wnt/β-catenin/GPX4， pre-tRNA-Arg-TCT/KEAP1/NRF2/xCT， mature-tRNA-Asp-GTC/ATF3/KEAP1/NRF2/xCT， and mature-tRNA-Asp-GTC/LPCAT3/ALOX15 axial expression was significantly aberrant after Gyp-L intervention （P<0.05）. ConclusionThe pre-tRNA-Arg-TCT/HMBS/Wnt/β-catenin/GPX4， pre-tRNA-Arg-TCT/KEAP1/Nrf2/xCT， mature-tRNA-Asp-GTC/ATF3/KEAP1/Nrf2/xCT， and mature-tRNA-Asp-GTC/LPCAT3/ALOX15 signaling pathways are involved in OC development. Gyp-L inhibits OC development by activating OVCAR3 cell ferroptosis onset mainly through the mature-tRNA-Asp-GTC/ATF3/KEAP1/Nrf2/xCT and mature-tRNA-Asp-GTC/LPCAT3/ALOX15 signaling axes.

ObjectiveWith the epidermal growth factor receptor（EGFR）/Signal Transducers and Activators of Transcription（STAT3）/Hexokinase 2（HK2） signaling pathway in atherosclerosis （AS） and ovarian cancer （OC） as the entry point， this paper discusses the molecular mechanism of Gypenoside L （Gyp-L） treating AS and OC with different diseases， provides a new perspective and theoretical basis for TCM treating AS and OC with EGFR-STAT3-HK2 pathway， and enriches the scientific connotation of the theory of "cytoskeleton in the heart". MethodsCCK-8 was used to detect the proliferation of HUVEC and OVCAR-3 cells， in order to determine the intervention concentration for subsequent experiments. The colorimetric method was used to detect the NO content in HUVEC and the contents of pyruvate and LDH in two cell lines. Cell cloning experiments and scratch experiments reflect the proliferation and migration ability of OVCAR-3 cells. Western blot was used to detect the expression levels of relevant proteins. Furthermore， two cell models overexpressing EGFR were constructed and co treated with Gyp-L. HUVEC cells were divided into control， ox-LDL， OE-NC， OE-EGFR， OE-NC+Gyp-L， and OE-EGFR+Gyp-L group. OVCAR-3 cells were divided into control， OE-NC， OE-EGFR ， OE-NC+Gyp-L， and OE-EGFR+Gyp-L group. The colorimetric method was used to detect the NO content in HUVEC and the contents of pyruvate and LDH in two cell lines. Western blot was used to detect the expression levels of EGFR-STAT3-HK2 pathway related proteins. Cell cloning experiments and scratch experiments reflect the proliferation and migration ability of OVCAR-3 cells. ResultsGyp-L can significantly reduce the NO content of HUVEC and the pyruvate and LDH content of two cell lines （P<0.05）； Inhibit the proliferation and migration ability of OVCAR-3 cells； Reduce the expression levels of EGFR/STAT3/HK2 pathway related proteins in HUVEC and OVCAR-3 cell lines （P<0.05）， and inhibit the glycolysis pathway. ConclusionGyp-L can inhibit glycolysis in HUVEC and OVCAR-3 cells through the EGFR/STAT3/HK2 pathway，thereby suppressing the occurrence and development of AS and OC.

Objective:To observe the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) at different frequencies on cognitive impairment due to high-altitude hypoxia.Methods:Sixty officers and soldiers displaying cognitive impairment in a hypoxic high-altitude environment were randomly divided into 15Hz, 20Hz and 25Hz groups, each of 20. They were given rTMS at those frequencies for 30 days. Before the stimulation and after 15 and 30 days, event-related potentials, latencies of mismatched negativity (MMN) and P300 signals were recorded. The participants′ cognition was also evaluated using the Montreal Cognitive Assessment Scale (MoCA). Correlation between the electrophysiological indexes and the MoCA scores was computed.Results:After 15 days, all had shorter MMN latencies, higher total MoCA scores and better memory scores. The only significant difference among the three groups was in the average memory scores. After 15 days, MMN latency was significantly negatively correlated with the memory scores in all three groups ( r=0.44 to -0.54). Conclusions:rTMS at frequencies above 15Hz can effectively relieve cognitive impairment, especially memory dysfunction, resulting from high-altitude hypoxia.

Objective:To analyze the epidemiological and clinical features of infectious diseases of the central nervous system (CNS).Methods:A cross-sectional study and analysis were conducted to summarize the epidemiological and clinical characteristics of 9 918 patients with CNS infectious diseases, who were diagnosed and treated at 29 hospitals across China from January 1, 2001 to December 31, 2020. Data collected included demographic data, clinical manifestations, health economic indicators, and prognostic outcomes.Results:Among the 9 918 collected cases of CNS infectious diseases, 5 559 were male (56.0%) and 4 359 were female (44.0%), with an onset age of 38 (25, 53) years. Education level: slightly more junior high school education (2 651 cases, 26.7%), and less elementary school education and below (2 181 cases, 22.0%) were found. Occupational distribution: farmers were found predominant (3 215 cases, 32.4%), followed by workers (1 826 cases, 18.4%) and students (1 633 cases, 16.5%). Clinical manifestations: headache (6 074 cases, 61.2%), fever (5 869 cases, 59.2%) and positive meningeal irritation signs (2 273 cases, 22.9%) were the 3 most common clinical manifestations, followed by nausea and (or) vomiting (2 095 cases, 21.1%), impaired consciousness (2 077 cases, 20.9%), psychiatric symptom (1 866 cases, 18.8%) and epilepsy (1 627 cases, 16.4%), etc., and cranial nerve involvement was found in 669 cases (6.7%). Major pathogens included viruses in 6 814 cases (68.7%), Mycobacterium tuberculosis in 1 677 cases (16.9%), common bacteria in 864 cases (8.7%), fungi in 254 cases (2.6%), spirochetes of syphilis in 183 cases (1.8%), parasites in 121 cases (1.2%), and rickettsiae in 5 cases (0.1%). Urban-rural distribution: slightly more cases were found in the countryside (5 418 cases, 54.6%) than in the towns (4 500 cases, 45.4%). Distribution of onset by season: 2 412 cases (24.3%) fell ill in spring, 2 835 cases (28.6%) in summer, 2 187 cases (22.1%) in fall, and 2 484 cases (25.0%) in winter. Health economics: the duration of hospitalization was 15 (8, 27) days, and the cost of hospitalization was 1.53 (0.91, 3.02)×10 000 yuan. Prognosis: 9 531 cases (96.1%) were cured or improved, and 92 cases (0.9%) died. Conclusions:The pathogens responsible for CNS infectious diseases are predominantly viruses. Although the incidence is slightly higher during the summer months, the overall seasonal pattern is not particularly pronounced. These infections are more commonly observed in young and middle-aged males and present with a diverse range of clinical manifestations, contributing to a significant disease burden.