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

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5^492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
Animals ; Disease Models, Animal ; Mice ; Protein Serine-Threonine Kinases/deficiency* ; Mutation/genetics* ; Epileptic Syndromes/genetics* ; Humans ; Dendritic Spines/pathology* ; Spasms, Infantile/genetics* ; Male ; Seizures/genetics* ; Mice, Inbred C57BL

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC. Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January 2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups. Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszel χ2 test,P<0.001,Pearson's R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%. Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Concurrent chemoradiotherapy (CCRT) refers to the simultaneous treatment of chemotherapy and radiotherapy, and the effect of radiotherapy is enhanced with low-dose chemotherapy, which can reduce tumor recurrence and metastasis and improve clinical prognosis of patients. At present, the main factors for the increase of radiosensitivity of concurrent chemotherapy is that concurrent chemotherapy prevents the repair of tumor cells, and chemotherapy and radiotherapy act on different cell cycles and have synergistic effects. However, even for patients with locally advanced cervical cancer (LACC) who have undergone CCRT, the 5-year survival rate is only 60%, which is still not ideal. In order to improve the efficacy, researchers have conducted a series of exploratory studies, which consist of the combination of targeted drugs and immunodrugs, and neoadjuvant regimens before CCRT, etc. Although targeted or immunologic drugs are effective treatment of LACC, in view of the lack of large-scale evidence-based medical evidence, multi-center prospective and randomized phase III clinical trials and high-level articles are needed to improve the level of evidence-based medicine. This consensus summarizes several key evidence-based medical studies published recently, especially the clinical research progress in targeted and immunological therapies, providing reference for domestic peers.

A combined full-scan mass spectrometry/data-dependent acquisition(Full MS/ddMS2)and full-scan mass spectrometry/parallel reaction monitoring(Full MS/PRM)approach for qualitative and quantitative analysis of plasma acylcarnitines was established on the basis of ultra-performance liquid chromatography-high resolution mass spectrometry(UPLC-HRMS).A total of 165 kinds of acylcarnitines were identified,and 111 kinds of acylcarnitines were quantified.The method demonstrated good reproducibility,with a relative standard deviation of less than 20%for plasma acylcarnitine content.Statistical analyses,including t-tests,partial least squares-discriminant analysis,variable importance in projection and volcano plot analysis,indicated significant alterations in plasma acylcarnitine levels in heart failure patients after myocardial infarction,for instance,46 kinds of acylcarnitines showing marked increases compared to myocardial infarction patients.Acylcarnitines showed a strong positive correlation with the clinical biomarker NT-proBNP,which was associated with heart failure.The combined use of acylcarnitine markers AC(C14-OH),AC(C12:1a),long-chain acylcarnitines,total acylcarnitines and NT-proBNP significantly enhanced the diagnostic sensitivity and specificity for post-infarction heart failure,with the area under the receiver operating characteristic curve(AUC)reaching 0.9456.The results of this work indicated that acylcarnitine was poised to become a crucial metabolic target for precise diagnosis,treatment and nutritional intervention in the progression of heart failure after myocardial infarction.

The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.
Humans ; Mice ; Animals ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Lung Neoplasms/metabolism* ; Acrylamides/pharmacology* ; ErbB Receptors/metabolism* ; Cell Line, Tumor ; CD47 Antigen/therapeutic use*

This study aimed to explore the potentiating effect and mechanism of the extract of Jingfang Granules(JFG) on the activation of macrophages. The RAW264.7 cells were treated with JFG extract and then stimulated by multiple agents. Subsequently, mRNA was extracted, and reverse transcription-polymerase chain reaction(RT-PCR) was used to measure the mRNA transcription of multiple cytokines in RAW264.7 cells. The levels of cytokines in the cell supernatant were detected by enzyme-linked immunosorbent assay(ELISA). In addition, the intracellular proteins were extracted and the activation of signaling pathways was determined by Western blot. The results showed that JFG extract alone could not promote or slightly promote the mRNA transcription of TNF-α, IL-6, IL-1β, MIP-1α, MCP-1, CCL5, IP-10, and IFN-β, and significantly enhance the mRNA transcription of these cytokines in RAW264.7 cells induced by R848 and CpG in a dose-dependent manner. Furthermore, JFG extract also potentiated the secretion of TNF-α, IL-6, MCP-1, and IFN-β by RAW264.7 cells stimulated with R848 and CpG. As revealed by mechanism analysis, JFG extract enhanced the phosphorylation of p38, ERK1/2, IRF3, STAT1, and STAT3 in RAW264.7 cells induced by CpG. The findings of this study indicate that JFG extract can selectively potentiate the activation of macrophages induced by R848 and CpG, which may be attributed to the promotion of the activation of MAPKs, IRF3, and STAT1/3 signaling pathways.
Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/metabolism* ; Plant Extracts/metabolism* ; Lipopolysaccharides/pharmacology* ; Macrophages ; Cytokines/metabolism* ; RNA, Messenger/metabolism*

OBJECTIVES: To investigate the cerebral metabolism in the patients with type 2 diabetes mellitus-associated cognitive dysfunction (T2DACD) and explore the mechanism of electroacupuncture (EA) at the acupoints for Tiaozang Xingshen (adjusting zangfu function and rescuing the spirit) in treatment of T2DACD, using magnetic resonance spectroscopy. METHODS: Fifteen patients with T2DACD (observation group) and 22 healthy subjects (control group) were enrolled. In the observation group, the patients were treated with EA for Tiaozang Xingshen at Baihui (GV 20) and Shenting (GV 24), and bilateral Feishu (BL 13), Pishu (BL 20), Shenshu (BL 23), Zusanli (ST 36), Sanyinjiao (SP 6), Hegu (LI 4) and Taichong (LR 3). EA was operated with disperse-dense wave, 2 Hz/100 Hz in frequency and 0.1 mA to 1.0 mA in current intensity; 30 min each time, once daily. One course of EA consisted of 5 treatments, at the interval of 2 days and the intervention lasted 8 courses. Before treatment in the control group, before and after treatment in the observation group, the score of Montreal cognitive assessment scale (MoCA), the score of clinical dementia rating (CDR), Flanker paradigm, Stroop paradigm, Nback paradigm, the score of self-rating anxiety scale (SAS), the score of self-rating depression scale (SDS), and the score of Hamilton depression rating scale (HAMD) were evaluated separately; the glycolipid metabolic indexes (fasting plasma glucose [FPG], glycosylated hemoglobin type A1c [HbA1c], total cholesterol [TC], triacylglycerol [TG], high-density lipoprotein cholesterol [HDL-C] and low-density lipoprotein cholesterol [LDL-C]) were determined；with the magnetic resonance spectroscopy technique adopted, the metabolites in the basal ganglia area were detected. The correlation analysis was performed for the metabolite values with MoCA score, CDR score , Flanker paradigm, Stroop paradigm, and Nback paradigm. RESULTS: Before treatment, compared with the control group, in the observation group, MoCA score was lower (P<0.001), CDR score and the levels of FPG and HbA1c were higher (P<0.001); the reaction times of Flanker non-conflict, Flanker conflict, Stroop neutrality, Stroop congruence, Stroop conflict, and 1-back were prolonged (P<0.05, P<0.001), and the accuracy of Flanker conflict, Stroop conflict, and 1-back decreased (P<0.05, P<0.01); the ratio of N-acetyl aspartate (NAA) to creatine (Cr) in the left basal ganglia area was dropped (P<0.001), and that of myo-inositol (MI) to Cr in the right side increased (P<0.05). In the observation group after treatment, compared with the levels before treatment, MoCA score was higher (P<0.001), the scores of CDR, SAS and HAMD were reduced (P<0.01, P<0.05), the reaction times of Flanker conflict and Stroop conflict shortened (P<0.001, P<0.05), and the accuracy of Flanker conflict and 1-back increased (P<0.001, P<0.05); the ratio of NAA to Cr in the left basal ganglia area and that of the gamma-aminobutyric acid (GABA) to Cr in the right increased (P<0.05), that of MI to Cr in the right decreased (P<0.05). Before treatment, in the observation group, the ratio of MI to Cr in the right basal ganglia area was positively correlated with the reaction time of Stroop congruence (r=0.671, P=0.012) and this ratio was positively correlated with the reaction time of Stroop conflict (r=0.576, P=0.039). CONCLUSIONS Electroacupuncture for "adjusting zangfu function and rescuing the mind" improves the cognitive function of T2DACD patients, which may be related to the regulation of NAA, MI and GABA levels in the basal ganglia.
Humans ; Electroacupuncture ; Acupuncture Therapy ; Acupuncture Points ; Diabetes Mellitus, Type 2/therapy* ; Glycated Hemoglobin ; Cognitive Dysfunction/therapy* ; Cholesterol ; gamma-Aminobutyric Acid