In January 2025， the European Society for Medical Oncology （ESMO） released the ESMO clinical practice guideline interim update on the management of biliary tract cancer as a supplementary update to Biliary tract cancer： ESMO clinical practice guideline for diagnosis， treatment and follow-up published in November 2022. This interim update mainly revises the latest evidence-based medical recommendations in the key fields of molecular diagnostics and clinical management since the release of the original guidelines， and it is not a comprehensive update of the entire document. This article summarizes and makes an excerpt of the new recommendations from this interim update.

The transcriptome sequencing based on Illumina Novaseq 6000 Platform was performed with the untreated seed embryo(DS), stratified seed embryo(SS), and germinated seed embryo(GS) of Zanthoxylum nitidum, aiming to explore the molecular mechanism regulating the seed dormancy and germination of Z. nitidum and uncover key differentially expressed genes(DEGs). A total of 61.41 Gb clean data was obtained, and 86 386 unigenes with an average length of 773.49 bp were assembled. A total of 29 290 DEGs were screened from three comparison groups(SS vs DS, GS vs SS, and GS vs DS), and these genes were annotated on 134 Kyoto Encyclopedia of Genes and Genomes(KEGG) pathways. KEGG enrichment analysis revealed that the plant hormone signal transduction pathway is the richest pathway, containing 226 DEGs. Among all DEGs, 894 transcription factors were identified, which were distributed across 34 transcription factor families. These transcription factors were also mainly concentrated in plant hormone signal transduction and mitogen-activated protein kinase(MAPK) signaling pathways. Further real-time quantitative polymerase chain reaction(RT-qPCR) validation of 12 DEGs showed that the transcriptome data is reliable. During the process of seed dormancy release and germination, a large number of DEGs involved in polysaccharide degradation, protein synthesis, lipid metabolism, and hormone signal transduction were expressed. These genes were involved in multiple metabolic pathways, forming a complex regulatory network for dormancy and germination. This study lays a solid foundation for analyzing the molecular mechanisms of seed dormancy and germination of Z. nitidum.
Zanthoxylum/metabolism* ; Plant Dormancy/genetics* ; Seeds/metabolism* ; Gene Expression Regulation, Plant ; Plant Proteins/metabolism* ; Transcriptome ; Gene Expression Profiling ; Germination ; Transcription Factors/metabolism* ; Plant Growth Regulators/genetics* ; Signal Transduction

Since the promulgation of the first Drug Administration Law of the People's Republic of China 40 years ago in 1984, China has undergone four main stages in the traditional Chinese medicine(TCM) regulation: the initial establishment of TCM regulation rules(1984-1997), the formation of a modern TCM regulatory system(1998-2014), the reform of the review and approval system for new TCM drugs(2015-2018), and the construction of a scientific regulation system for TCM(2019-2024). Over the past five years, a series of milestone achievements of TCM regulation in China have been achieved in the six aspects, including its strategic objectives and the establishment of a science-based regulatory system, the reform of the review and approval system for new TCM drugs, the optimization and improvement of the TCM standard system and its formation mechanism, comprehensive enhancement of regulatory capabilities for TCM safety, international harmonization of TCM regulation and its role in promoting innovation. Looking ahead, centered on advancing TCMRS to establish a sound regulatory framework tailored to the unique characteristics of TCM, TCM regulation will evolve into new reform patterns, advancing and extending across eight critical fronts, including the legal framework and policy architecture, the review and approval system for new TCM drugs, the quality standard and management system of TCM, the comprehensive quality & safety regulation and traceability system, the research and transformation system for TCMRS, AI-driven innovations in TCM regulation, the coordination between high-quality industrial development and high-level regulation, and the leadership in international cooperation and regulatory harmonization. In this way, a unique path for the development of modern TCM regulation with Chinese characteristics will be pioneered.
Humans ; China ; Drugs, Chinese Herbal/standards* ; History, 20th Century ; History, 21st Century ; Medicine, Chinese Traditional/trends*

OBJECTIVE: To explore the neuroprotective effects of Xuefu Zhuyu Decoction (XFZYD) based on in vivo and metabolomics experiments. METHODS: Traumatic brain injury (TBI) was induced via a controlled cortical impact (CCI) method. Thirty rats were randomly divided into 3 groups (10 for each): sham, CCI and XFZYD groups (9 g/kg). The administration was performed by intragastric administration for 3 days. Neurological functions tests, histology staining, coagulation and haemorheology assays, and Western blot were examined. Untargeted metabolomics was employed to identify metabolites. The key metabolite was validated by enzyme-linked immunosorbent assay and immunofluorescence. RESULTS: XFZYD significantly alleviated neurological dysfunction in CCI model rats (P<0.01) but had no impact on coagulation function. As evidenced by Evans blue and IgG staining, XFZYD effectively prevented blood-brain barrier (BBB) disruption (P<0.05, P<0.01). Moreover, XFZYD not only increased the expression of collagen IV, occludin and zona occludens 1 but also decreased matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 (COX-2), which protected BBB integrity (all P<0.05). Nine potential metabolites were identified, and all of them were reversed by XFZYD. Adenosine was the most significantly altered metabolite related to BBB repair. XFZYD significantly reduced the level of equilibrative nucleoside transporter 2 (ENT2) and increased adenosine (P<0.01), which may improve BBB integrity. CONCLUSIONS XFZYD ameliorates BBB disruption after TBI by decreasing the levels of MMP-9 and COX-2. Through further exploration via metabolomics, we found that XFZYD may exert a protective effect on BBB by regulating adenosine metabolism via ENT2.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Blood-Brain Barrier/metabolism* ; Brain Injuries, Traumatic/metabolism* ; Adenosine/metabolism* ; Male ; Rats, Sprague-Dawley ; Rats

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Peri-implant keratinized mucosa (PIKM) augmentation refers to surgical procedures aimed at increasing the width of PIKM. Consensus reports emphasize the necessity of maintaining a minimum width of PIKM to ensure long-term peri-implant health. Currently, several surgical techniques have been validated for their effectiveness in increasing PIKM. However, the selection and application of PIKM augmentation methods may present challenges for dental practitioners due to heterogeneity in surgical techniques, variations in clinical scenarios, and anatomical differences. Therefore, clear guidelines and considerations for PIKM augmentation are needed. This expert consensus focuses on the commonly employed surgical techniques for PIKM augmentation and the factors influencing their selection at second-stage surgery. It aims to establish a standardized framework for assessing, planning, and executing PIKM augmentation procedures, with the goal of offering evidence-based guidance to enhance the predictability and success of PIKM augmentation.
Humans ; Consensus ; Dental Implants ; Mouth Mucosa/surgery* ; Keratins

OBJECTIVE To evaluate the cost-effectiveness of the first-line treatment using the combination therapy of sugemalimab and chemotherapy （hereinafter referred to as the “combination therapy”） for advanced esophageal squamous cell carcinoma （ESCC） with high programmed death-ligand 1 （PD-L1） expression from the perspective of the Chinese healthcare system. METHODS A partitioned survival model was constructed based on data from the GEMSTONE-304 study. The model cycle was set at 3 weeks， with a study duration of 10 years and a discount rate of 5%. The primary output parameters of the model included total costs， quality-adjusted life year （QALY）， incremental costs， and incremental cost-effectiveness ratio （ICER）. Cost- utility analysis was employed to assess the economic feasibility of the combination therapy compared to chemotherapy alone. The robustness of the base case analysis results was evaluated through univariate sensitivity analysis， probabilistic sensitivity analysis， and scenario analysis. RESULTS The ICER of the combination therapy compared to chemotherapy alone was 288 430.35 yuan/QALY， significantly exceeding the willingness-to-pay （WTP） threshold of 173 354.52 yuan/QALY which was set at 1.94 times the per capita gross domestic product （GDP） in 2023. The price of sugemalimab was the primary factor influencing the ICER. When the WTP threshold was set at 1.94 times the per capita GDP （173 354.52 yuan/QALY）， the probability of the combination therapy being cost-effective compared to chemotherapy alone was 0. The combination therapy only became cost-effective compared to chemotherapy alone when the price of the drug dropped to 6 107.41 yuan per box （600 mg）. CONCLUSIONS From the perspective of the Chinese healthcare system， the combination therapy for first-line treatment of advanced ESCC with high PD-L1 expression is not cost-effective； the combination therapy is cost-effective when the price of sugemalimab decreas by 50.65%.

Objective:To compare the short-term outcomes of very low birth weight (VLBW) and extremely low birth weight (ELBW) infants supplementarily fed with fortified donor human milk (DHM) or preterm formula (PF) when the mother's own milk (MOM) is insufficient.Methods:This retrospective cohort study included 91 VLBW or ELBW preterm infants with birth weight<1 500 g who were hospitalized in Peking Union Medical College Hospital from October 1, 2017, to September 30, 2020. Based on the supplemental feeding method when MOM was insufficient, these infants were divided into the DHM group ( n=51) and PF group ( n=40). Mann-Whitney U, t-test, Chi-square test, or Fisher's exact test were used to compare the short-term clinical outcomes during hospitalization between the two groups. Results:(1) There were no statistically significant differences between the 91 preterm infants in the DHM group and PF group in their gestational age, birth weight, sex ratio, birth mode, mothers' age at delivery, or the proportion of infants of small gestational age (all P>0.05). (2) The feeding volume in the DHM group was significantly greater than that in the PF group on the 14th day after birth [(108.2±53.1) vs. (81.0±47.8) ml/(kg·d), t=0.78, P=0.020]. Moreover, the time to achieve the feeding amounts up to 120 ml/(kg·d) and 150 ml/(kg·d) for infants in the DHM group were significantly shorter than those in the PF group [(17.5±10.2) vs. (30.0±12.0) d, t=4.38; (22.1±13.3) vs. (32.3±11.9) d, t=0.02; both P<0.05]; (3) Lower proportion of peripherally inserted central catheter (PICC) [58.8% (30/51) vs. 100% (40/40), χ 2=21.88, P<0.001] and shorter PICC duration were observed in the DHM group [10.0 (0.0-19.0) vs. 29.0 (17.0-40.5) d, Z=5.56, P<0.001] compared to the PF group. The times of red blood cell transfusions and the incidence of late sepsis in the DHM group were less than those in the PF group [0.0 (0.0-2.0) vs. 2.0 (1.0-3.0) times, Z=4.44, P<0.001; 23.5% (12/51) vs. 50.0% (20/40), χ 2=6.39, P=0.011]. There were no statistically significant differences observed in the incidence of bronchopulmonary dysplasia, neonatal necrotizing enterocolitis, retinopathy of prematurity, and the length of hospitalization (all P>0.05). Conclusion:When MOM is insufficient, supplementing VLBW and ELBW infants with fortified donor human milk can shorten the time to achieve enteral nutrition and reduce the use rate and time of PICC, the incidence of late-onset sepsis, and the times of red blood cell transfusion.

Objective:To observe the clinical efficacy and safety of Tongren Niuhuang Qingxin Pills combined with telmisartan tablets in the treatment of hypertensive vertigo syndrome of phlegm-heat disturbance.Methods:Randomized controlled trial was conducted. Totally 80 patients with hypertension vertigo and phlegm-heat disturbance syndrome were selected from March 2021 to August 2022 at Beijing Tongrentang Hospital of Traditional Chinese Medicine as the observation objects. They were randomly divided into two groups using a random number table method, with 40 cases in each group. The control group received oral telmisartan tablets, while the experimental group received Tongren Niuhuang Qingxin Pills in addition to the control group. Both groups were treated for 28 days and followed up for 1 month. The patients' room blood pressure before and after treatment was measured, and TCM syndrome scores were evaluated. The dizziness assessment rating scale (DARS) was used to evaluate the severity of dizziness, adverse reactions during treatment were recorded, drug safety was observed, and clinical efficacy was evaluated.Results:The total effective rate of the experimental group was 85.0% (34/40), and that of the control group was 7.5% (3/40), with statistical significance between the two groups ( χ2=48.32, P<0.001). Compared with before treatment, the experimental group had SBP [(136.63 ± 6.01) mmHg vs. (159.30 ± 9.01) mmHg, t=-21.00] and DBP [(84.48 ± 4.36) mmHg vs. (95.30 ± 3.75) mmHg, t=-13.80] after treatment; after treatment, SBP [(137.34 ± 6.39) mmHg vs. (158.00 ± 10.06) mmHg, t=-5.28] and DBP [(86.08 ± 4.43) mmHg vs. (95.18 ± 6.61) mmHg, t=-8.09] decreased in the control group ( P<0.01), but there was no statistical significance between the two groups after treatment ( P>0.05). After treatment, the TCM syndrome scores in the experimental group (8.68 ± 3.39 vs. 15.12 ± 3.03, Z=-6.61) were lower than those in the control group ( P<0.001), and DARS score [(8.53 ± 3.93) vs. (12.20 ± 3.95), Z=-3.63] was lower than that in the control group ( P<0.001). After treatment, the therapeutic effect index of TCM syndromes in the experimental group improved compared to before treatment in the same group. The therapeutic effect index of each symptom, from high to low, was as follows: rotation of oneself or visual objects>numbness of limbs>dry stool>dizziness and dizziness>liking cold drinks>bitter and dry mouth>red urine>red tongue, yellow coating, and greasy tongue>vomiting sticky and turbid phlegm>tinnitus>smooth pulse. There were no significant adverse reactions during the treatment of the two groups. Conclusion:Tongren Niuhuang Qingxin Pills combined with telmisartan can reduce the blood pressure of patients with hypertensive vertigo syndrome of phlegm-heat disturbance, improve the vertigo symptoms and TCM syndromes of patients, and the efficacy evaluation is superior to that of telmisartan alone.

Objective:Abnormal programmed cell death in immune cells is associated with autoimmune diseases,but the patterns of programmed cell death in systemic lupus erythematosus(SLE)and especially lupus nephritis(LN)remain unclear.This study aims to explore the association between SLE,LN,and immune cell death patterns. Methods:Bulk RNA sequencing(bulk RNA-seq)and single-cell RNA sequencing(scRNA-seq)data were downloaded from the Gene Expression Omnibus(GEO)database.Bioinformatic analysis was conducted to explore the expression levels of genes related to 3 cell death patterns in peripheral blood mononuclear cells of SLE patients.Key cell subsets involved in the imbalance of cell death patterns were identified through scRNA-seq.Immunofluorescence was used to detect the expression levels of receptor interacting serine/threonine kinase 3(RIPK3),mixed-lineage kinase domain-like protein(MLKL),phosphorylated MLKL(pMLKL),caspase 1(CASP1),CD1c molecule(CD1C),C-type lectin domain containing 9A(CLEC9A),and X-C motif chemokine receptor 1(XCR1)in dendritic cells(DC).scRNA-seq was performed on kidney tissues collected from LN patients and healthy controls(HC)at the Third Xiangya Hospital of Central South University,followed by bioinformatic analysis to identify key cell subsets involved in the imbalance of cell death patterns.Pseudotime analysis and ligand-receptor analysis were used to explore the differentiation direction and cell communication of different DC subsets.Transient transfection was used to transfect RAW264.7 cells with empty plasmid,empty plasmid+dsDNA(HSV-DNA),empty plasmid+200 μmol/L tert-butyl hydroperoxide(TBHP),stimulator of interferon genes(STING)shRNA plasmid,STING shRNA plasmid+dsDNA(HSV-DNA),and STING shRNA plasmid+200 μmol/L TBHP.Annexin V-mCherry and SYTOX Green staining were used to detect cell death in each group.Western blotting was used to detect the activation of CASP1,gasdermin D(GSDMD),RIPK3,and MLKL in each group. Results:Bioinformatic analysis showed an imbalance in 3 cell death patterns in SLE and LN patients:Pro-inflammatory pyroptosis and necroptosis were activated,while anti-inflammatory apoptosis was inhibited.The key cell subsets involved were DC subsets,particularly focusing on CLEC9A+cDC1.Immunofluorescence results showed that the expression levels of RIPK3,MLKL,and CASP1 in DCs were higher in the SLE group compared to the HC group.pMLKL and CASP1 expression levels in renal cDC1 marked by CLEC9A and XCR1 were higher in the LN group than in the HC group.Pseudotime analysis and ligand-receptor analysis suggested that the CLEC9A+cDC1 subset in LN kidney tissues originated from peripheral circulation.Annexin V-mCherry and SYTOX Green staining results showed that the number of dead cells decreased in the STING shRNA transfection group compared to the empty plasmid group in RAW264.7 cells.Western blotting results showed that the activation of CASP1,GSDMD,RIPK3,and MLKL was decreased in the STING shRNA transfection group compared to the empty plasmid group. Conclusion:This study provides novel insights into the role of CLEC9A+cDC1 in the imbalance of cell death patterns in SLE and LN.