ObjectiveTo improve the therapeutic effect of Buyang Huanwutang（BYHW） on diabetic kidney disease （DKD） and explore new methods for developing new Chinese medicine decoctions，we utilized 5-hydroxymethylcytosine （5hmC）-Seal sequencing technology and network pharmacology to modify BYHW. MethodsWe selected 14 diabetes mellitus （DM） patients and 15 DKD patients hospitalized in the Department of Endocrinology of Peking University Third Hospital in 2021. Circulating free DNA （cfDNA） in the patients’ plasma was sequenced. After data processing and screening， we performed temporal clustering analysis to select a DKD 5hmC gene set， which was then cross-validated with a DKD database gene set to obtain the DKD gene set. We retrieved target genes of the seven herbal components of BYHW from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and the Encyclopedia of Traditional Chinese Medicine （ETCM）， and performed cross-analysis with the DKD gene set to identify common genes shared by the disease and the Chinese medicines. A protein-protein interaction （PPI） network was constructed for the common genes to screen out the key genes. Chinese medicines targeting these key genes were searched against ETCM to identify removable Chinese medicines. Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis was performed on non-common DKD genes， and key genes in DKD-related pathways were selected based on machine learning. The GSE30529 dataset was used to verify the expression trends of 5hmC-modified genes and the feasibility of target genes as drug targets. TCMBank was used to search for target genes and obtain compounds targeting these genes and the corresponding Chinese medicines to construct a "key target-compound-Chinese medicine" network. Molecular docking was employed to verify the binding affinity of compounds with key targets. TCMSP and ETCM were used to search and count the candidate Chinese medicines targeting DKD-related genes， and a new decoction was formed by adding the selected Chinese medicines. A mouse model of DKD was established to examine the efficacy of the new decoction based on the mouse body mass， random blood glucose， urinary microalbumin （mALB）， serum creatinine （Scr）， and blood urea nitrogen （BUN） and by hematoxylin-eosin staining， periodic acid-Schiff staining， Masson staining， immunofluorescence assay， and Real-time PCR. ResultsThe cross-analysis results showed that the DKD gene set included 507 genes， of which 30 were target genes of BYHW. The PPI analysis indicated that the top 15% target genes regarding the degree were interleukin-6 （IL-6）， Toll-like receptor 4 （TLR4）， lactotransferrin （LTF）， lipoprotein lipase （LPL）， and sterol regulatory element-binding transcription factor 1 （SREBF1）. Persicae Semen and Pheretima in BYHW were unrelated to key genes and removed. Machine learning identified 10 potential target genes， among which TBC1 domain family member 5 （TBC1D5）， RAD51 paralog B （RAD51B）， and proteasome 20S subunit alpha 6 （PSMA6） had expression trends consistent with the GSE30529 dataset and could serve as drug targets. The "key target-compound-Chinese medicine" network and molecular docking results indicated that the compounds with good binding affinity to target proteins were arginine， glycine， myristicin， serine， and tyrosine， corresponding to 121 Chinese medicines. The top 10 Chinese medicines targeting DKD-related genes were Lycii Fructus， Ginseng Radix et Rhizoma， Dioscoreae Rhizoma， Rehmanniae Radix Praeparata， Isatidis Radix， Glehniae Radix， Ophiopogonis Radix， Allii Sativi Bulbus， Isatidis Folium， and Bolbostemmatis Rhizoma. Based on traditional Chinese medicine theory， the new decoction was obtained after removal of Persicae Semen and Pheretima and addition of Rehmanniae Radix Praeparata and Dioscoreae Rhizoma. Animal experiment results indicated that the modified BYHW improved the kidney function and inhibited renal fibrosis in DKD mice， with better effects than the original decoction. ConclusionThe BYHW modified based on 5hmC-Seal sequencing demonstrates better performance in inhibiting fibrosis and ameliorating DKD than the original decoction. This elucidates the biomedical theory behind the epigenetic modification of traditional Chinese medicine prescriptions， potentially offering new perspectives for the exploration of these prescriptions

ObjectiveTo improve the therapeutic effect of Buyang Huanwutang（BYHW） on diabetic kidney disease （DKD） and explore new methods for developing new Chinese medicine decoctions，we utilized 5-hydroxymethylcytosine （5hmC）-Seal sequencing technology and network pharmacology to modify BYHW. MethodsWe selected 14 diabetes mellitus （DM） patients and 15 DKD patients hospitalized in the Department of Endocrinology of Peking University Third Hospital in 2021. Circulating free DNA （cfDNA） in the patients’ plasma was sequenced. After data processing and screening， we performed temporal clustering analysis to select a DKD 5hmC gene set， which was then cross-validated with a DKD database gene set to obtain the DKD gene set. We retrieved target genes of the seven herbal components of BYHW from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and the Encyclopedia of Traditional Chinese Medicine （ETCM）， and performed cross-analysis with the DKD gene set to identify common genes shared by the disease and the Chinese medicines. A protein-protein interaction （PPI） network was constructed for the common genes to screen out the key genes. Chinese medicines targeting these key genes were searched against ETCM to identify removable Chinese medicines. Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis was performed on non-common DKD genes， and key genes in DKD-related pathways were selected based on machine learning. The GSE30529 dataset was used to verify the expression trends of 5hmC-modified genes and the feasibility of target genes as drug targets. TCMBank was used to search for target genes and obtain compounds targeting these genes and the corresponding Chinese medicines to construct a "key target-compound-Chinese medicine" network. Molecular docking was employed to verify the binding affinity of compounds with key targets. TCMSP and ETCM were used to search and count the candidate Chinese medicines targeting DKD-related genes， and a new decoction was formed by adding the selected Chinese medicines. A mouse model of DKD was established to examine the efficacy of the new decoction based on the mouse body mass， random blood glucose， urinary microalbumin （mALB）， serum creatinine （Scr）， and blood urea nitrogen （BUN） and by hematoxylin-eosin staining， periodic acid-Schiff staining， Masson staining， immunofluorescence assay， and Real-time PCR. ResultsThe cross-analysis results showed that the DKD gene set included 507 genes， of which 30 were target genes of BYHW. The PPI analysis indicated that the top 15% target genes regarding the degree were interleukin-6 （IL-6）， Toll-like receptor 4 （TLR4）， lactotransferrin （LTF）， lipoprotein lipase （LPL）， and sterol regulatory element-binding transcription factor 1 （SREBF1）. Persicae Semen and Pheretima in BYHW were unrelated to key genes and removed. Machine learning identified 10 potential target genes， among which TBC1 domain family member 5 （TBC1D5）， RAD51 paralog B （RAD51B）， and proteasome 20S subunit alpha 6 （PSMA6） had expression trends consistent with the GSE30529 dataset and could serve as drug targets. The "key target-compound-Chinese medicine" network and molecular docking results indicated that the compounds with good binding affinity to target proteins were arginine， glycine， myristicin， serine， and tyrosine， corresponding to 121 Chinese medicines. The top 10 Chinese medicines targeting DKD-related genes were Lycii Fructus， Ginseng Radix et Rhizoma， Dioscoreae Rhizoma， Rehmanniae Radix Praeparata， Isatidis Radix， Glehniae Radix， Ophiopogonis Radix， Allii Sativi Bulbus， Isatidis Folium， and Bolbostemmatis Rhizoma. Based on traditional Chinese medicine theory， the new decoction was obtained after removal of Persicae Semen and Pheretima and addition of Rehmanniae Radix Praeparata and Dioscoreae Rhizoma. Animal experiment results indicated that the modified BYHW improved the kidney function and inhibited renal fibrosis in DKD mice， with better effects than the original decoction. ConclusionThe BYHW modified based on 5hmC-Seal sequencing demonstrates better performance in inhibiting fibrosis and ameliorating DKD than the original decoction. This elucidates the biomedical theory behind the epigenetic modification of traditional Chinese medicine prescriptions， potentially offering new perspectives for the exploration of these prescriptions

Lymph node metastasis (LNM) is a crucial risk factor influencing an unfavorable prognosis in specific cancers. Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets. Nevertheless, the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments. Preclinical models, in this context, serve as the conduit connecting fundamental theories to clinical outcomes. In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms. Using various experimental animals, including mice, diverse methods, such as carcinogen-induced tumorigenesis, tumor cell line or human tumor transplantation, genetic engineering, and humanization, have been used effectively to construct numerous models for tumor LNM. Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis. Transplantation models, using human tumor cell lines or patient-derived tumors, offer a research platform closely mirroring the histology and clinical behavior of human tumors. Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment. Humanized models are used to overcome barriers between human and murine immune systems. Beyond mouse models, various other animal models have unique advantages and limitations, all contributing to exploring LNM. This review summarizes existing in vitro and animal preclinical models, identifies current bottlenecks in preclinical research, and offers an outlook on forthcoming preclinical models.
Animals ; Humans ; Mice ; Lymphatic Metastasis/pathology* ; Disease Models, Animal ; Cell Line, Tumor

Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon (RAP). Despite its therapeutic effects, the surgical risk and unclear mechanism hamper the clinical application. Numerous evidences support macrophages as the key immune cells during bone remodeling. Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1^CreERT2; R26^GFP lineage tracing system. Fluorescence staining, flow cytometry analysis, and western blot determined the significantly enhanced expression of binding immunoglobulin protein (BiP) and emphasized the activation of sensor activating transcription factor 6 (ATF6) in macrophages. Then, we verified that macrophage specific ATF6 deletion (ATF6^f/f; CX3CR1^CreERT2 mice) decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy. In contrast, macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement. In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6. At the mechanism level, RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfα promotor and augmenting its transcription. Additionally, molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element (ERSE). Taken together, ATF6 may aggravate orthodontic bone remodeling by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
Animals ; Mice ; Macrophages/metabolism* ; Tumor Necrosis Factor-alpha/genetics* ; Tooth Movement Techniques/methods* ; Activating Transcription Factor 6/metabolism* ; Bone Remodeling ; Flow Cytometry ; Blotting, Western

Objective to analyze the Budget Execution Rate of administrative departments in sample hospitals,and to realize the cost control of Budget performance integration with Balanced Score Card(BSC)Financial Dimension Quantitative Assessment.Methods The budget and execution data of 23 administrative departments were collected from January to June in the sample 2023.The budget execution rate was calculated and cleaned,and the data were segmented by histogram.Using the financial dimension 25 to divide by the total number of items in each department's budget to obtain the scoreof each item in each department,and using the interpolation method to calculate the cost scores of each department,then into the performance appraisal.Results(1)Each item score should be multiplied by item coefficient,and then sum up;(2)The total score of self-executing Project+the total score of centralized executing project.(3)Cost score:1 the scores of 8 departments of non-homing items were 5.54～15.76,2 the scores of 15 departments of homing items were 7.68～17.06.Conclusion It adopts the concept of BSC and Hospital Resource Planning as the cost control of administrative departments to make up for the lack of qualitative and quantitative BSC;can focus on monitoring the dispersion of large data;histogram score results of segmentation objective and easy to operate,makes the interpolation calculation more credible.In a word,it provides quantitative ideas and methods in the aspects of different responsibilities and difficult performance evaluation.

Objective The study aimed to investigate the impact of rare earth elements(REEs)exposure on pregnancy outcomes of in vitro fertilization-embryo transfer(IVF-ET)by analyzing samples from spouses. Methods A total of 141 couples were included.Blood and follicular fluid from the wives and semen plasma from the husbands,were analyzed for REEs using inductively coupled plasma mass spectrometry(ICP-MS).Spearman's correlation coefficients and the Mann-Whitney U test were used to assess correlations and compare REE concentrations among three types of samples,respectively.Logistic models were utilized to estimate the individual REE effect on IVF-ET outcomes,while BKMR and WQS models explored the mixture of REE interaction effects on IVF-ET outcomes. Results Higher La concentration in semen(median 0.089 ng/mL,P=0.03)was associated with a lower fertilization rate.However,this effect was not observed after artificial selection intervention through intracytoplasmic sperm injection(ICSI)(P=0.27).In semen,the REEs mixture did not exhibit any significant association with clinical pregnancy. Conclusion Our study revealed a potential association between high La exposure in semen and a decline in fertilization rate,but not clinical pregnancy rate.This is the first to report REEs concentrations in follicular fluid with La,Ce,Pr,and Nd found at significantly lower concentrations than in serum,suggesting that these four REEs may not accumulate in the female reproductive system.However,at the current exposure levels,mixed REEs exposure did not exhibit reproductive toxicity.

Objective to analyze the Budget Execution Rate of administrative departments in sample hospitals,and to realize the cost control of Budget performance integration with Balanced Score Card(BSC)Financial Dimension Quantitative Assessment.Methods The budget and execution data of 23 administrative departments were collected from January to June in the sample 2023.The budget execution rate was calculated and cleaned,and the data were segmented by histogram.Using the financial dimension 25 to divide by the total number of items in each department's budget to obtain the scoreof each item in each department,and using the interpolation method to calculate the cost scores of each department,then into the performance appraisal.Results(1)Each item score should be multiplied by item coefficient,and then sum up;(2)The total score of self-executing Project+the total score of centralized executing project.(3)Cost score:1 the scores of 8 departments of non-homing items were 5.54～15.76,2 the scores of 15 departments of homing items were 7.68～17.06.Conclusion It adopts the concept of BSC and Hospital Resource Planning as the cost control of administrative departments to make up for the lack of qualitative and quantitative BSC;can focus on monitoring the dispersion of large data;histogram score results of segmentation objective and easy to operate,makes the interpolation calculation more credible.In a word,it provides quantitative ideas and methods in the aspects of different responsibilities and difficult performance evaluation.

Objective to analyze the Budget Execution Rate of administrative departments in sample hospitals,and to realize the cost control of Budget performance integration with Balanced Score Card(BSC)Financial Dimension Quantitative Assessment.Methods The budget and execution data of 23 administrative departments were collected from January to June in the sample 2023.The budget execution rate was calculated and cleaned,and the data were segmented by histogram.Using the financial dimension 25 to divide by the total number of items in each department's budget to obtain the scoreof each item in each department,and using the interpolation method to calculate the cost scores of each department,then into the performance appraisal.Results(1)Each item score should be multiplied by item coefficient,and then sum up;(2)The total score of self-executing Project+the total score of centralized executing project.(3)Cost score:1 the scores of 8 departments of non-homing items were 5.54～15.76,2 the scores of 15 departments of homing items were 7.68～17.06.Conclusion It adopts the concept of BSC and Hospital Resource Planning as the cost control of administrative departments to make up for the lack of qualitative and quantitative BSC;can focus on monitoring the dispersion of large data;histogram score results of segmentation objective and easy to operate,makes the interpolation calculation more credible.In a word,it provides quantitative ideas and methods in the aspects of different responsibilities and difficult performance evaluation.

Objective to analyze the Budget Execution Rate of administrative departments in sample hospitals,and to realize the cost control of Budget performance integration with Balanced Score Card(BSC)Financial Dimension Quantitative Assessment.Methods The budget and execution data of 23 administrative departments were collected from January to June in the sample 2023.The budget execution rate was calculated and cleaned,and the data were segmented by histogram.Using the financial dimension 25 to divide by the total number of items in each department's budget to obtain the scoreof each item in each department,and using the interpolation method to calculate the cost scores of each department,then into the performance appraisal.Results(1)Each item score should be multiplied by item coefficient,and then sum up;(2)The total score of self-executing Project+the total score of centralized executing project.(3)Cost score:1 the scores of 8 departments of non-homing items were 5.54～15.76,2 the scores of 15 departments of homing items were 7.68～17.06.Conclusion It adopts the concept of BSC and Hospital Resource Planning as the cost control of administrative departments to make up for the lack of qualitative and quantitative BSC;can focus on monitoring the dispersion of large data;histogram score results of segmentation objective and easy to operate,makes the interpolation calculation more credible.In a word,it provides quantitative ideas and methods in the aspects of different responsibilities and difficult performance evaluation.

Objective To analyze the efficacy and safety of transurethral resection of bladder neck combined with intraoperative and postoperative regular injection of triamcinolone acetonide in the treatment of bladder neck contracture(BNC)after radical prostatectomy(RP).Methods Clinical data of 19 patients with BNC after RP who underwent transurethral resection of bladder neck combined with intraoperative and postoperative regular triamcinolone acetonide treatment in our hospital during Mar.2018 and Mar.2023 were retrospectively analyzed.The changes in international prostate symptom score(IPSS),quality of life score(QoL)and complications were analyzed before operation,3 and 12 months after operation,and at the end of follow-up.Results All patients completed the follow-up,10 of whom received one treatment.Of the 9 patients with recurrence,6 received 2 treatments(including 2 cases of recurrence after surgery)and 1 received 3 treatments.After a mean follow-up of 3 years,the success rate of one treatment was 52.6％(10/19),and the cumulative success rate was 73.7％(14/19).The IPSS and QoL at each follow-up time point were significantly improved compared with those before surgery(P＜0.05).Postoperative complications included epididymitis in 2 cases(10.5％),transient hematuria in 2 cases(10.5％),and urinary incontinence in 11 cases(57.9％),including 6 new cases of urinary incontinence,and 5 cases whose urinary incontinence lasted to the end of follow-up.Conclusion Bladder neck resection combined with intraoperative and postoperative regular triamcinolone acetonide injection has a successful rate of 73.7％in the treatment of BNC after RP.However,some patients require multiple operations,and the incidence of postoperative urinary incontinence is high and the recovery is slow.