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 clinical value of plasma insulin-like factor 6(INSL6)in predicting the risk of acute aortic syndromes(AAS)and adverse outcomes.Methods A retrospective case-control trial was conducted on 194 AAS patients admitted to Department of Cardiovascular Diseases of Second Affiliated Hospital of Army Medical University between April 2021 and June 2023.Another 194 sex-,age-and BMI-matched individuals without aortic diseases were recruited from the health examination center between December 2021 and January 2024.Their plasma INSL6 level was measured with ELISA,and the general clinical data and results of some laboratory tests were collected and compared between the 2 groups.Spearman correlation analysis was used to assess the relationship between plasma INSL6 and other variables,receiver operating characteristic(ROC)curve was plotted to evaluate the diagnostic efficacy of INSL6 for AAS occurrence,multivariate conditional logistic regression model was utilized to analyze the association between plasma INSL6 and AAS onset,and Kaplan-Meier survival curve and multivariate Cox proportional hazards regression model was applied to analyze the relationship between acute-phase plasma INSL6 level and adverse prognosis in AAS patients.Results The plasma INSL6 level was significantly higher in AAS patients at acute phase than the control individuals[704.40(481.32～1 152.62)vs 141.24(107.60～163.72)pg/mL,P<0.001],but no statistical difference was observed in the level among the patients with different AAS subtypes(aortic dissection,intramural hematoma,and penetrating aortic ulcer).Spearman correlation analysis showed that the plasma INSL6 level was positively correlated with platelet count(r=0.325,P<0.001)and hemoglobin concentration(r=0.186,P=0.009),and negatively with IL-6(r=-0.182,P=0.011),INF-γ(r=-0.283,P<0.001),and D-dimer levels(r=-0.195,P=0.006).Multivariate conditional logistic regression analysis revealed that plasma INSL6 level was independently associated with the occurrence of AAS(OR=28.634,95%CI:7.267～112.820,P<0.001).ROC curve analysis further confirmed that the optimal cutoff value of plasma INSL6 in predicting AAS was 259.425 pg/mL,with a sensitivity of 95.9%and a specificity of 98.5%at this threshold.Kaplan-Meier curve analysis demonstrated that AAS patients with low INSL6 level had significantly lower cumulative survival rates(P=0.020)and event-free survival rates(P=0.004)than those with high INSL6 level(P<0.05).Multivariate COX regression analysis revealed that,after adjusting for sex,age,systolic blood pressure,ST classification,and surgical treatment,acute-phase INSL6 level was independently associated with all-cause mortality(HR:0.999,95%CI:0.999～1.000,P=0.023),AAS-related mortality(HR:0.999,95%CI:0.998～1.000,P=0.012),and composite endpoint events(HR:0.999,95%CI:0.999～1.000,P=0.026)in AAS patients during follow-up.Conclusion Plasma INSL6 level is closely associated with the occurrence and adverse prognosis of AAS,and the indicator is expected to be an effective biomarker for diagnosing AAS and predicting its prognosis.

Objective To identify genetic regulators of ionizing radiation(IR)sensitivity through clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease 9(Cas9)genome-wide screening.Methods A specialized single guide RNA(sgRNA)library was developed targeting 987 stress-response regulatory genes identified through Kyoto Encyclopedia of Genes and Genomes(KEGG),Reactome and gene ontology(GO)databases,followed by construction of sgRNA plasmids and packaging into a lentiviral library.Using colon adenocarcinoma Caco-2 cells as a model system,the Cas9-stable transgenic line was established via lentiviral transduction and antibiotic selection.Library-transduced cells underwent puromycin selection,followed by γ-irradiation(dose optimized via preliminary experiments).Post-irradiation phenotypic selection was conducted after 14 days,with subsequent next-generation sequencing of surviving cell populations to identify enriched/depleted sgRNAs.Candidate genes were functionally validated through orthogonal assays:cell counting kit-8(CCK-8)proliferation analysis,clonogenic survival assays and flow cytometric quantification of reactive oxygen species(ROS)and apoptotic markers.Results The optimized screening platform identified 281 radiation response genes(165 radiosensitive and 116 radioprotective candidates).Functional validation revealed Bcl2-associated athanogene 3(BAG3)knockdown significantly enhanced radioresistance.Proliferation was increased 1.2-1.5 fold,clonogenic survival improved 1.5-2.0 fold,and ROS was reduced by 13％-25％coupled with 32％-73％apoptosis attenuation compared to control groups.Conclusion The integrated CRISPR/Cas9 screening platform effectively identifies novel radiation response regulators,as evidenced by the discovery of BAG3 as a critical radiosensitivity determinant.This high-throughput functional genomics approach provides a robust methodology for systematically mapping molecular determinants of cellular radiation response,with potential applications in both mechanistic studies and therapeutic target discovery.

Objective:To investigate the attitude of neonatologists toward the treatment of extremely preterm infants (EPIs) in China.Methods:A cross-sectional survey was conducted using a questionnaire designed and posted on Wenjuanxing, a web-based survey platform, from June to July 2021. The respondents were neonatal physicians in various provinces and cities in China. The questionnaire covered the basic information, treatment experience and attitude towards EPIs, and opinions on the current definition of the preterm infant in China. The results were described or analyzed using the Chi-square test.Results:A total of 1 066 valid replies were collected. The respondents included 322 males and 744 females, among whom 78.1% (832/1 066) were assistant director physicians or director physicians, 82.8% (882/1 066) were from tertiary hospitals, and 83.0% (885/1 066) had the experiences of treating EPIs. In terms of the attitude toward the treatment of EPIs, 63.0% (672/1 066) of the respondents suggested that the lower limit of gestational age for EPIs requiring active resuscitation should be defined at 25 gestational weeks or less. Moreover, 57.1% (609/1 066) considered that the current domestic definition of preterm infants as 28 gestational age or above was inappropriate, and 75.2% (458/609) considered that the lower limit defined as preterm infants should be 25 gestational weeks or less. Concerning the treatment experience in EPIs, 54.3% (579/1 066) of the respondents suggested that in their hospital, withdrawing treatment in EPIs was common or very common, and 83.3% (888/1 066) considered that the main reason for withdrawing treatment was family members' concerns about the prognosis. Those who hesitated about treating the EPIs accounted for 71.6% (763/1 066), and 83.9% (640/763) hesitated due to the poor prognosis and possible medical disputes. Moreover, 32.7% (349/1 066) of the respondents or their colleagues had been involved in medical disputes about whether to treat EPIs, and 74.8% (797/1 066) believed that the patients should be the decision-maker on whether to treat EPIs or not.Conclusion:Most neonatal physicians in this survey hold a positive attitude toward the treatment of EPIs and believe that the lower limit of gestational age for preterm infants should be lowered. However, a hesitating attitude to the care of EPIs is still common, and uncertainty about the prognosis of EPIs remains a concern.

Objective:To analyze the clinical characteristics of adult Chinese patients with syncope.Methods:This is a cross-sectional survey study. Patients with preliminary diagnosis of syncope in the Emergency Department, Geriatrics and Cardiology Outpatient Department, or Syncope Unit of 37 hospitals in 19 provinces, autonomous regions and the Hong Kong Special Administrative Region from June 2018 to March 2021 were included in this study. The clinical features of these patients with syncope were analyzed.Results:A total of 4 950 consecutive patients with syncope were included in this study. The age was (56.3±16.8)years, and 2 604 cases (52.6%) were male. The most common type of syncope was neurally mediated syncope (2 345 (47.4%)), followed by cardiac syncope (1 085 (21.9%)), orthostatic hypotensive syncope (311 (6.3%)), and unexplained syncope accounted for nearly one third (1 155 (23.3%)). Predisposing syncope was more common in patients under 65 years of age(2 066(72.4%) vs. 786(27.6%),χ 2=136.5, P<0.001). Presyncope was more common in patients with neurally mediated syncope (1 972(79.0%) vs.1 908(73.9%), χ 2=17.756, P<0.001). Premonitory symptoms were more common in women(1 837(80.0%) vs. 1 863(73.0%),χ 2=33.432, P<0.001). Presyncope syndrome was more common in patients under 65 years of age (2 482(77.8%) vs. 1 218(73.4%),χ 2=17.523, P=0.001). Cyanosis was more common in ≥65 years old patients (271(18.2%) vs. 369(12.7%), χ 2=23.235, P<0.001). Urinary incontinence was more common in old patients aged ≥65 years(252(15.2%) vs. 345(10.8%), χ 2=19.313, P<0.001). Family history was more common in patients with cardiogenic syncope compared with other types of syncope (264(24.3%) vs. 754(19.5%), χ 2=11.899, P=0.001). Hypertention(1 480(30.5%)), coronary heart disease(1 057(21.4%)), atrial flutter and atrial fibrillation(359(7.2%)), second degree atrioventricular block(236(4.8%)) were common complications of syncope. The proportion of patients with coronary heart disease was significantly higher in cardiac syncope than that of other types of syncope(417(38.4%) vs. 640(16.6%), χ 2=241.376, P<0.001). Other common complications included cerebrovascular diseases (551 (11.1%)) and diabetes mellitus (632(12.8%)). Conclusions:Neurally mediated syncope is the most common syncope in adult Chinese population. Patients with predisposing conditions and premonitory conditions are younger. Presyncope is more common in women. The proportion of family history and coronary heart disease is higher in patients with cardiogenic syncope.

Objective:To explore the correlations between 11C-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (CFT) microPET/CT imaging and the degree of damage to dopamine neurons in the substantia nigra of midbrain and the severity of Parkinson′s disease (PD). Methods:Sixty male Sprague-Dawley (SD) rats were divided into PD model group ( n=48) and control group ( n=12) by random number table method. The PD model was established by injecting 6-hydroxydopamine (6-OHDA) into the right striatum. The rotational behavior test and 11C-CFT microPET/CT imaging were performed at 1, 2, 3 and 4 weeks after the establishment of PD model. The radioactivity uptake values of bilateral striatum were analyzed and the radioactivity uptake ratio of injured side to healthy side was calculated. The number of tyrosine hydroxylase (TH) immunoreactive positive neurons in the pars compacta of substantia nigra was counted by immunofluorescence staining, and the ratio of total number of TH positive neurons in injured side to healthy side was calculated. Data were analyzed by one-way analysis of variance, the least significant difference t test and Pearson correlation analysis. Results:At 1, 2, 3 and 4 weeks after the establishment of PD model, the rotation speed of PD model to the healthy side was (4.55±1.37), (8.64±1.64), (9.96±1.83) and (11.67±2.77) r/min, respectively, while there was no rotation behavior in the control group. Meanwhile, the ratios of 11C-CFT uptake and the number of TH positive neurons in the PD model group were 0.658±0.038, 0.580±0.094, 0.513±0.042, 0.394±0.065 and 0.698±0.066, 0.604±0.062, 0.546±0.064, 0.315±0.082, respectively, which were significantly lower than those in the control group (0.997±0.048 and 0.996±0.054; F values: 167.50, 169.20, both P<0.05). Correlation analysis showed that 11C-CFT uptake ratio was correlated with rotation behavior (rotation speed) and TH positive neuron ratio ( r values: -0.877, 0.897, both P<0.001). Conclusion:In the PD animal model, the ratios of 11C-CFT uptake has a good correlation with the degree of damage to dopamine neurons in the substantia nigra of the midbrain (TH positive neuron ratio) and the severity of PD.

This article reviews the present situation, progress, challenges, and the future developments for the screening and diagnosis of inherited metabolic disease (IMD) in both domestic and abroad in clinical practice, aiming to improve the screening and diagnosis system of IMD in China and to provide a reference for clinicians to increase the diagnosis and cure rate of treatable IMD, and promote the development of this field.

In order to provide efficient medical care to atrial fibrillation patients in the community, the Huamu Community Health Service Center in association with its medical consortium, Renji Hospital have developed a novel atrial fibrillation management system. With the collaboration of general practitioners and specialist team from the tertiary hospital, a special clinic for atrial fibrillation has been set up in the community health service center, which is based on the internet technology and the medical consortium platform. This article introduces the development of this novel system and the initial outcome of the measures, to provide a reference for the management of atrial fibrillation patients in the community.

Objective To explore the research hotspots and trends in the field of CSCs through the bibliometric analysis of the literature on CSCs. Methods Based on the core database of Web of Science, CiteSpace was used to analyze the annual distribution of published articles, authors, institutions, countries, journals, citations and keywords, and to explore the frequency, centrality and clustering of key words. Results (1) A total of 8131 articles were included after screening. China was the country with the largest number of articles, and Sun Yat-Sen University was the organization with the largest number of articles; (2) The hot spots in the field of CSCs are the research of CSCs in breast cancer and pancreatic cancer, the research of CSCs sorting and identification of molecular markers ALDH and genes PTEN, Sox2, C-myc, EZH2, the mechanism of EMT inducing the production of CSCs and promoting tumor metastasis, cellular and molecular mechanisms of CSCs resistance to chemical, radiation and targeted drug attacks, Wnt/β-catenin signaling pathway and tumor microenvironment regulate the differentiation of CSCs and targeted inhibition of CSCs in the treatment of malignant tumors; (3) The research trend of CSCs is CSCs stem research-biological mechanism of CSCs-CSCs application in the treatment of cancer. Conclusion The focus and direction of CSCs research are EMT inducing CSCs to promote tumor metastasis, CSCs resisting chemical attack, mesenchymal stem cells regulating CSCs, the metabolism of CSCs, and inhibitors targeting CSCs at present and in the future.

Objective To investigate the research hotspots and trends in the field of immunotherapy for liver cancer in 2011-2020 based on bibliometric methods. Methods The Web of Science-SCI Expanded database was searched with the following search strategy: #1 TS = (Liver Neoplasms OR Neoplasms, Hepatic OR Neoplasms, Liver OR Liver Neoplasm OR Neoplasm, Liver OR Hepatic Neoplasms OR Hepatic Neoplasm OR Neoplasm, Hepatic OR Cancer of Liver OR Hepatocellular Cancer OR Cancers, Hepatocellular OR Hepatocellular Cancers OR Hepatic Cancer OR Cancer, Hepatic OR Cancers, Hepatic OR Hepatic Cancers OR Liver Cancer OR Cancer, Liver OR Cancers, Liver OR Liver Cancers OR Cancer of the Liver OR Cancer, Hepatocellular) AND #2 TS = (Immunotherapy OR Immunotherapies OR Immunity therapy); time span: 2011-2020; type of literature: Article; language: English. CiteSpace software was used to perform a visualized analysis of the articles in the field of immunotherapy for liver cancer published in 2011-2020 from the aspects of the distributions of year, country, institution, author, journal, and fund, times cited, and keywords, and the frequency, centrality, and clustering of keywords were discussed. Results A total of 1972 articles on immunotherapy for liver cancer were included, and the analysis showed that China was the country with the largest number of articles, Sun Yat-sen University was the institution with the largest number of articles, and Journal for Immunotherapy of Cancer was the journal with the largest number of articles. The research hotspots in this field included tumor-associated macrophages, oncolytic virus (such as adenovirus), tumor vaccine therapy, adoptive cellular immunotherapy, immune checkpoint inhibitors, and combined immunotherapy. The trend of this field was tumor vaccine therapy → immunotherapy for oncolytic virus → adoptive cellular immunotherapy → immune checkpoint inhibitor therapy. Conclusion Immunotherapy for liver cancer has undergone continuous development in the recent ten years, and with the research and development of tumor vaccine therapy, oncolytic virus, and immune checkpoint inhibitors and the improvement of immune checkpoint inhibitors, combined treatment based on immunotherapy is expected to further improve the clinical outcome of liver cancer.