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

OBJECTIVES: To study the impact of SURF4 expression level on long-term prognosis of gastric cancer (GC) and biological behaviors of GC cells. METHODS: SURF4 expression level in GC and its association with long-term patient prognosis were analyzed using publicly available databases and in 155 GC patients with low and high SURF4 expressions detected immunohistochemically. The Cox proportional hazard model and Kaplan-Meier survival curves were used to analyze independent prognostic predictors of GC and the 5-year survival rate of the patients with different SURF4 expression levels. Informatics analyses were conducted to explore the correlation of SURF4 expression level with immune cell infiltration in GC, SURF4-related differential genes and their associated pathways. In cultured GC cell line HGC-27, the effects of SURF4 knockdown and overexpression on proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were investigated. RESULTS: Analysis of GEPIA dataset and immunohistochemical results suggested significant SURF4 overexpression in GC (P<0.05), which was associated with shortened 5-year survival time of the patients (χ²=38.749, P<0.001). The prognosis of GC was closely related to tumor stage T3-4, N2-3, CEA≥5 μg/L and CA19-9≥37 kU/L (P<0.05). SURF4 expression level was negatively correlated with activated B cells, NK cells and CD8⁺ effector memory T cells (P<0.05) and positively correlated with CD4⁺ T cells (P<0.05). GO and KEGG enrichment analysis suggested that SUFR4 may participate in GC carcinogenesis by promoting EMT through the tight junction pathway. In HGC-27 cells, SURF4 overexpression significantly decreased E-cadherin expression, increased N-cadherin expression, inhibited ZO-1 and claudin-1 expressions, and promoted cell proliferation, migration and invasion. CONCLUSIONS SURF4 is highly expressed in GC, and its overexpression is associated with a shortened 5-year survival of the patients possibly by enhancing tumor cell proliferation, migration and invasion via inhibiting tight junction proteins and promoting EMT.
Humans ; Stomach Neoplasms/metabolism* ; Cell Proliferation ; Cell Movement ; Epithelial-Mesenchymal Transition ; Cell Line, Tumor ; Neoplasm Invasiveness ; Prognosis ; Tight Junction Proteins/metabolism* ; Membrane Proteins/metabolism* ; Female ; Male

Objective Utilizing a specially engineered miR-144-GFP-H1 human embryonic stem cell(hESC)reporter line,this study leverages GFP fluorescence as an indicator of miR-144 expression to gauge the progression of erythropoiesis.The investigation is aimed at elucidating the potential roles of lncRNAs within the erythropoietic framework and conducting an initial assessment of their functional impact.Methods The miR-144/451-GFP-H1 cell line(hereafter referred to as 144-H1)was utilized for in vitro erythrocyte induction culture.The subpopulations of cells entering the erythropoiesis stage were characterized by the surface molecules CD71 and GPA.The GFP reporter gene of miR-144 served as a critical determi-nant to distinguish between GFP-positive cells(with a high propensity for erythropoiesis)and GFP-negative cells(with a low propensity for erythropoiesis).Transcriptome sequencing was performed on both groups to identify differentially ex-pressed long non-coding RNAs(lncRNAs).LncRNA entries with potential for validation were selected for preliminary func-tional verification.The CRISPR/Cas9 gene editing technique was employed to design functional interference strategies for the targeted lncRNAs,obtaining 144-H1 cell lines with knocked-out function of the specific lncRNAs.These knockout cell lines,along with non-knockout 144-H1 cell lines,were used for parallel erythrocyte induction culture to identify differential nodes.This approach preliminarily verified their impact on erythropoiesis in an in vitro development model.Results 1)The constructed 144-H1 cell line was capable of expressing GFP fluorescence upon entering the stage of in vitro erythrocyte in-duction,indicating the activation of miR-144/451.2)Within the CD71,GPA double-positive group,significant differences in lncRNA expression were observed between the GFP-positive and GFP-negative subpopulations.3)Gene editing strategies involving the deletion of sequence segments capable of effectively interfering with the function of multiple lncRNA entries were designed and verified for successful editing.In the knockout cell lines,parts of the lncRNA sequences were directly de-leted.4)In parallel validation experiments of erythrocyte induction culture,cell lines with LINC01569 knocked out exhibited significant differences in flow cytometric subpopulations and cell proliferation capabilities compared to the non-knockout cell lines:①The knockout cell lines showed sustained high expression of GFP fluorescence.②The proportion of the CD71-GPA double-positive group in the knockout cell lines continuously decreased during erythrocyte maturation.③No significant ex-pression of hemoglobin was observed in the knockout cell lines,lacking the characteristic red color.④The cell proliferation capability of the knockout cell lines was significantly lower than that of the non-knockout cell lines(P＜0.05).Conclusion The successful employment of the 144-H1 cell line facilitated an exploration into the potential functions of lncRNAs in e-rythropoiesis.This enables the design of more refined in vitro developmental experiments to enhance the precision in captu-ring lncRNA functions.Among the differentially expressed lncRNA entries,LINC01569 was preliminarily validated to play a regulatory role in erythropoiesis.The functional absence of LINC01569 severely impacts the normal differentiation and prolif-eration of erythrocytes.The specific regulatory mechanism of LINC01569 in erythropoiesis warrants further investigation and research.

The essence of clinical practice guidelines lies in their recommendations. It is common to find strong recommendations supported by low-quality evidence in current published guidelines. There is a typical misunderstanding among medical professionals that without high-quality evidence, it is impossible to develop high-quality guidelines or only expert consensus can be developed. Based on the GRADE approach, this paper explains the concept and clinical significance of low-quality evidence, and introduces the methods for formulating recommendations based on low-quality evidence in guidelines, with the aim to provide reference for guideline developers and users in China.

As one of the pathogenic mechanisms contained in The Inner Canon of Yellow Emperor （《黄帝内经》）， “disease with latent pathogen induced by a new pathogen” means that the induced new pathogen resulted to a combination of the latent previous pathogen and the new pathogen， which caused the disease. Based on this， it is believed that the change of “nodule-cancer transformation” of pulmonary nodules is actually based on the deficiency of original qi， and the new pathogen induces the latent pathogens like phlegm coagulation， qi stagnation， blood stasis， toxicity， so healthy qi can not drive the pathogens out， and the long-time detention generated into cancerous turbidity， and deve-loped into cancerous tumour at the end. Therefore， based on the three-stage treatment of unformed cancer， dense cancerous toxin， and developed cancer， the clinical practice applied six methods of clearing， expelling， dissipating， tonifying， harmonizing， and transforming， taking into account both the manifestation and root cause， moving the treatment window of pulmonary nodules forward， attacking the pathogens when the toxin was not yet overbearing， supporting the healthy qi before declining， delaying the process of nodules-cancer transformation， and providing ideas for the prevention and treatment of pulmonary nodules “nodule-cancer transformation” in traditional Chinese medicine.

Objective:To carry out clinical and genetic analysis for a child featuring Brain-Lung-Thyroid syndrome (BLTS).Methods:A child who had presented at the Children′s Hospital Affiliated to Shandong University on May 27, 2022 was selected as the study subject. Clinical data was collected. Trio-whole exome sequencing (Trio-WES) was carried out for the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child was given individualized treatment following the diagnosis.Results:The child, a two-year-and-seven-month-old boy, had presented with global developmental delay, ataxia and hypothyroidism. WES revealed that he has harbored a heterozygous c. 674C>T variant of the NKX2-1 gene, based on which he was diagnosed with BLTS. CT scan revealed interstitial and parenchymal inflammation in his lungs, which was reduced by budesonide aerosol inhalation. Conclusion:Discovery of the novel c. 674C>T variant has enriched the mutational spectrum of the NKX2-1 gene. Budesonide aerosol may be used to treat lung inflammation associated with BLTS.

Objective To explore the morphological symmetry of the anterior circulation cerebral arteries based on digital subtraction angiography(DSA),and to analyze the value of arterial walking route on the healthy side in guiding catheterization in endovascular treatment for patients with sick-side major artery occlusion of the anterior circulation.Methods A total of 250 consecutive patients who underwent cerebral angiography at the Shengli Oilfield Central Hospital of China between January 2021 and August 2022 were enrolled in this study as angiography group,which was subdivided into youth angiography subgroup(＜50 years),middle-aged angiography subgroup(50-69 years),and elderly angiography subgroup(≥70 years).Other 170 patients with acute occlusion of the anterior circulation vessels,who received emergency mechanical thrombectomy,were collected as thrombectomy group.After successful recanalization,the cerebral angiographic imaging findings of both groups,including the arterial walking route symmetry of bilateral C1 segment,C2-C3 segment,ophthalmic segment,M1 segment proximal to the bifurcation,and M1 segment distal to the bifurcation,were analyzed and compared between the two groups.The recanalization rate and the consistency of bilateral arterial walking route in the thrombectomy group were also analyzed.Results No statistically significant differences in the arterial walking route of the C1 segment,C2-C3 segment,ophthalmic segment,M1 segment proximal to the bifurcation,and M1 segment distal to the bifurcation existed between the left side and right side(all P＞0.05).Ordinary bilateral symmetry was observed in M1 segment proximal to the bifurcation,and excellent bilateral symmetry was observed in all the other segments.There were no statistically significant differences in the bilateral arterial walking route of the C1 segment,C2-C3 segment,ophthalmic segment,M1 segment proximal to the bifurcation,and M1 segment distal to the bifurcation between each other among the three subgroups(all P＞0.05).Ordinary bilateral symmetry of the C1 segment was observed in the youth angiography subgroup,ordinary bilateral symmetry of the M1 segment proximal to the bifurcation was observed in all three subgroups,and excellent bilateral symmetry was observed in all the other segments.In the thrombectomy group the recanalization rate was 95.5％and the consistency rate of bilateral arterial walking route was 89.0％.Conclusion Bilateral symmetry exists in the C1 segment,C2-C3 segment,ophthalmic segment,M1 segment proximal to the bifurcation,and M1 segment distal to the bifurcation of the anterior circulation cerebral arteries.These findings provide a reliable basis of referring healthy-side arterial walking route to guide catheterization in endovascular treatment for mechanical thrombectomy and recanalization of sick-side major artery occlusion of the anterior circulation.(J Intervent Radiol,2024,33:472-478)

OBJECTIVE: To explore the role of the Notch signaling pathway in regulating neuronal differentiation and sensorimotor ability in a zebrafish model of fetal alcohol spectrum disorder. METHODS: Zebrafish embryos treated with DMSO or 50 μmol/L DAPT (a Notch signaling pathway inhibitor) were examined for mortality rate, hatching rate, malformation rate, and body length at 15 days post fertilization (dpf). The mRNA expression levels of sox2, neurogenin1 and huc in the treated zebrafish embryos were detected using in situ hybridization and qRT-PCR, and their behavioral responses to strong light and vibration stimulation were observed. The zebrafish embryos were then exposed to DMSO, 1.5% ethanol, DAPT, or both ethanol and DAPT, and the changes in mRNA expression levels of sox2, neurogenin1, huc, and the Notch signaling pathway genes as well as behavioral responses were evaluated. RESULTS: Exposure to 50 μmol/L DAPT significantly increased the mortality rate of 1 dpf zebrafish embryos (P < 0.01), decreased the hatching rate of 2 dpf embryos (P < 0.01), increased the malformation rate of 3 dpf embryos (P < 0.001), and reduced the body length of 15 dpf embryos (P < 0.05). DAPT treatment significantly downregulated sox2 mRNA expression (P < 0.01) and increased neurogenin1 (P < 0.05) and huc (P < 0.01) mRNA expressions in zebrafish embryos. The zebrafish with DAPT treatment exhibited significantly shortened movement distance (P < 0.001) and lowered movement speed (P < 0.05) in response to all the stimulation conditions. Compared with treatment with 1.5% ethanol alone, which obviously upregulated notch1a, her8a and NICD mRNA expressions in zebrafish embryos (P < 0.05), the combined treatment with ethanol and DAPT significantly increased neurogenin1 and huc mRNA expression, decreased sox2 mRNA expression (P < 0.01), and increased the moving distance and moving speed of zebrafish embryos in response to strong light stimulation (P < 0.05). CONCLUSION Ethanol exposure causes upregulation of the Notch signaling pathway and impairs neuronal differentiation and sensorimotor ability of zebrafish embryos, and these detrimental effects can be lessened by inhibiting the Notch signaling pathway.
Animals ; Zebrafish ; Amyloid Precursor Protein Secretases ; Dimethyl Sulfoxide ; Platelet Aggregation Inhibitors ; Antineoplastic Agents ; Ethanol/adverse effects* ; Signal Transduction

Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases. CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that CYP1A1/2 knockout (KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO rats. Further studies found that the lipogenesis pathway (LXRα-SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhibited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. Our findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia.