Age-related macular degeneration (AMD) seriously endangers the visual health of the elderly, and its incidence rate is on the rise in recent years.As the aging of the population intensifies, the incidence rate of AMD will continue to rise.Therefore, it is crucial to explore its genetic pathogenic mechanism.Genome-wide association studies (GWAS) have identified a large number of single nucleotide polymorphisms associated with AMD.However, most of these polymorphisms are located in noncoding regions, and their functions are unclear.Therefore, revealing the regulatory effects of the genetic variations on gene expression, protein levels, and metabolite abundance serves as a powerful tool for deciphering the functions of noncoding variations discovered in GWAS.Furthermore, combining quantitative trait loci (QTLs) with GWAS can effectively explain GWAS data and increase the likelihood of discovering statistically significant genetic variation loci.This review summarizes research on the analysis and integration of GWAS combined with QTL data, aiming to better understand the impact of gene variations on the occurrence and development of AMD, thereby providing new ideas for searching for effective therapeutic targets for AMD.

OBJECTIVE To establish a core competency evaluation system for drug clinical trial quality management personnel in China and validate its application. METHODS Based on the scope of work， responsibilities， and role positioning of quality management personnel in drug clinical trials， a preliminary draft of the core competency evaluation system was constructed through literature analysis and expert consultation. The draft was refined through a Delphi method involving 17 experts who provided feedback and revisions， ultimately forming a complete evaluation system. The developed system was applied to conduct electronic surveys from March to May 2024 among 110 quality management personnel from 38 drug clinical trial institutions， comparing their scores on indicator importance and self-assessed capabilities. RESULTS The response rate of both rounds of questionnaire survey was 100%， with Kendall’s W coefficients of 0.256 and 0.277 （P＜0.001 for both）， and an expert authority coefficient of 0.946. The finalized evaluation system for core competencies of clinical trial quality management personnel comprised 9 primary indicators， covering individual professional competence， communication skills， implementation condition verification， informed consent process review， clinical trial execution monitoring， adverse event disposal， reporting and documentation， trial record examination， trial report auditing， and inspection of other tasks， and 107 secondary indicators. Empirical research revealed significant discrepancies between importance scores and self-assessed competency scores across 70 indicators among 110 respondents （P＜0.05）. Indicators with relatively notable gaps between importance scores and self-assessed competency scores included in-depth understanding of Good Clinical Practice （GCP） requirements （0.34-point gap）， familiarity with national and institutional clinical trial inspection priorities （0.24-point gap），etc. CONCLUSIONS The indicator system constructed in this study has good scientificity and reliability. Clinical trial quality management personnel demonstrate deficiencies in multiple critical competencies， highlighting the urgent need for targeted training programs to enhance their overall professional capabilities.

Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC50)of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal"dead ends"and"safe bets"for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogen-oxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.

Objective:To evaluate the efficacy and safety of baricitinib combined with ruxolitinib cream in the treatment of progressive nonsegmental vitiligo.Methods:Clinical data were retrospectively collected from patients with progressive nonsegmental vitiligo in Boao Super Hospital. All the patients were treated with oral baricitinib daily (2 mg/day for patients weighing ≤ 50 kg; 4 mg/day for those > 50 kg) in combination with topical application of ruxolitinib cream twice daily for 24 consecutive weeks. Disease severity was assessed using the facial vitiligo area scoring index (F-VASI) and total body VASI (T-VASI) at baseline, week 12, and week 24. Adverse reactions were monitored throughout the treatment course.Results:Six patients with progressive nonsegmental vitiligo were collected, including 3 males and 3 females, aged 26 - 42 years, with the disease duration ranging from 0.5 to 25 years. At week 12, 3 patients achieved a 50% ~ < 75% improvement in facial vitiligo lesions (F-VASI 50), 1 patient achieved F-VASI 75 (75% ~ < 90% improvement), and 1 patient achieved T-VASI 50; at week 24, 4 patients achieved F-VASI 50, 1 patient achieved F-VASI 75, 1 patient achieved F-VASI 90 (≥ 90% improvement), and 3 patients achieved T-VASI 50. During the treatment, upper respiratory infection occurred in 1 patient, acne in 1 patient, pruritus in 2 patients, elevation of total cholesterol levels in 2 patients, and increase of high-density lipoprotein levels in 2 patients. No severe adverse events were observed during the treatment.Conclusion:The combination therapy with baricitinib and ruxolitinib cream may have potential efficacy and safety in the treatment of progressive nonsegmental vitiligo.

Objective:To investigate the expression of interleukin (IL)-22 in lung adenocarcinoma and its effect and possible mechanism for lung adenocarcinoma metastasis.Methods:The cancer tissues and paired adjacent normal tissues (>2 cm from the tumor edge) surgically removed from 27 lung adenocarcinoma patients in Tianjin Medical University Cancer Institute & Hospital from January to June 2023 were retrospectively collected. Flow cytometry was used to detect the expression levels of IL-22 in T cells of all tissues, and the expression levels of IL-22 in T cells were compared between cancer and adjacent tissues, as well as between lung cancer tissues of patients with and without lymph node metastasis. The cancer tissues and paired adjacent normal tissues were retrospectively collected from 6 patients with lung adenocarcinoma during the same period, and the expression level of IL-22 receptor IL-22RA1 in the tissues was detected by Western blotting. IL-22RA1 transcriptome data from cancer tissues of lung adenocarcinoma patients in 3 datasets in The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database were collected. Using the R software survminer package to select the optimal critical value of IL-22RA1 that reflected the survival relationship, and patients were divided into high and low IL-22RA1 groups based on this. The survival package was used to draw the overall survival curve and log-rank test was performed for inter group comparison. Recombinant IL-22 was used to treat human lung adenocarcinoma A549 cells and mouse lung adenocarcinoma LLC cells, with cells not treated with IL-22 as controls; Transwell assay was used to detect the number of migrating cells in each group; Western blotting was used to detect the expression levels of ERK, AKT and STAT signaling pathways-related proteins, matrix metalloproteinase 9 (MMP-9) and epithelial cadherin (E-cad) in each group of cells. The expression levels of these proteins in A549 cells and LLC cells were also measured after the addition of STAT3 inhibitor C188-9, AKT inhibitor MK-2206 and ERK inhibitor SCH772984. A lung metastasis model of LLC cells was constructed using 10 C57BL/6 mice, the mice were randomly divided into the experimental group and the control group using simple randomization method. IL-22 neutralizing antibody (50 μg/mouse) and non-neutralizing control antibody (50 μg/mouse) were injected once every other day. On the 10th day, the mice were euthanized and dissected to count lung metastatic nodules. The metastatic lung tissue was stained with HE and the metastatic foci were counted. Flow cytometry was used to detect the proportion of CD4 + T cells and CD8 + T cells to immune cells in single cells prepared from metastatic lung tissue. Results:The flow cytometry analysis showed that the proportion of IL-22 + CD4 + T cells in T cells (labeled with CD3 and CD45) in 27 clinically collected lung adenocarcinoma tissues [ M ( Q1, Q3)] was higher than that in adjacent normal tissues [0.28% (0.04%, 1.00%) vs. 0.01% (0.00%, 0.25%)]. The proportion of IL-22 + CD4 + T cells in lung adenocarcinoma tissues of patients with metastasis (9 cases) was higher than that of patients without metastasis (18 cases) [1.06% (0.49%, 4.72%) vs. 0.15% (0.00%, 0.35%)], and the differences were statistically significant (both P < 0.01). Western blotting analysis showed that the relative expression level of IL-22RA1 protein in lung adenocarcinoma tissues was higher than that in adjacent normal tissues (1.03±0.25 vs. 0.35±0.10), and the difference was statistically significant ( P < 0.05). The overall survival of the IL-22RA1 low expression group in lung adenocarcinoma tissues was better than that of the IL-22RA1 high expression group in the TCGA database and GEO databases GSE42127, GSE29016 and GSE26939 datasets, and the differences were statistically significant (all P < 0.001). Transwell assay showed that A549 cells [(744±40) cells, (770±64) cells vs. (403±42) cells] and LLC cells [(167±39) cells, (246±80) cells vs. (31±5) cells] treated with 100 and 200 ng/ml IL-22 for 24 hours had fewer migration numbers than the control group, and the differences were statistically significant (both P < 0.01). Western blotting analysis showed that during treatment with 100 ng/ml recombinant IL-22 for 15-1 440 minutes, the levels of p-STAT3, p-ERK and p-AKT proteins in A549 and LLC cells were higher than those in the control group, while there was no difference in the levels of E-cad and MMP-9 proteins between the two groups. After the combined treatment of recombinant IL-22 and STAT3, AKT or ERK inhibitor, the corresponding levels of p-STAT3, p-AKT and p-ERK proteins in A549 and LLC cells were similar to those in cells without inhibitor and recombinant IL-22 treatment, but significantly lower than those in cells treated with recombinant IL-22 alone. In the dissected lung tissues of mice lung metastasis models, the experimental group had fewer metastatic lung nodules than the control group (2.3±0.6 vs. 7.0±2.0), and the difference was statistically significant ( t = 3.88, P = 0.018). In the morphological observation of lung metastasis tissues, the experimental group had fewer metastatic lesions than the control group (1.8±0.8 vs. 5.4±1.1), and the difference was statistically significant ( t = 5.69, P < 0.001). Flow cytometry analysis showed that the proportion of CD8 + T cells in immune cells in the lung tissues of mice in the experimental group (labeled with CD45) was higher than that in the control group [(27±5)% vs. (15±5)%], and the difference was statistically significant ( t = 3.01, P = 0.040). There was no statistically significant difference in the proportion of CD4 + T cells in immune cells between the two groups ( P > 0.05). Conclusions:The expression levels of IL-22 and its receptor IL-22RA1 in lung adenocarcinoma tissues are higher than those in adjacent normal tissues, and the high expression level of IL-22RA1 in cancer tissues may be associated with poor prognosis of patients; on the one hand, IL-22 may promote the migration of lung adenocarcinoma cells by activating the ERK, AKT and STAT3 signaling pathways, and on the other hand, it may promote lung adenocarcinoma metastasis by reducing CD8 + T cell infiltration in the immune microenvironment of lung adenocarcinoma.

Objective:To explore the aperiodic components(1/f slopes)and their associations with cognitive impairment in patients with schizophrenia.Methods:Nineteen patients with schizophrenia according to the Interna-tional Statistical Classification of Diseases and Related Health Problem,Tenth Revision(ICD-10)and 21 normal controls were administrated the total Brief Assessment of Cognition in Schizophrenia(BACS)to measure the cogni-tive performance.The 5-minute eyes-closed and eyes-open resting EEG signals were collected and parameterized in-to aperiodic components(1/f slope).Finally,Pearson correlation was used to examine the relationships between the 1/f slope and cognition assessment scores.Results:The patients with schizophrenia had higher 1/f slope compared to HC on central location of scalp(P＜0.05).The vocal memory scores showed a significantly positive relation with 1/f slopes in patients with schizophrenia(anterior location:r=-0.68,P＜0.05;central location:r=-0.44,P＜0.05),but a significantly negative relation in normal controls(anterior location:r=0.57,P＜0.05;posterior lo-cation:r=0.54,P＜0.05).Conclusion:The 1/f slopes of EEG in schizophrenia were steeper than normal control,suggesting its strong cognitive functional significance and complex mechanisms in schizophrenia.

Objective:To investigate the impact of various conditions on the adsorption of quetiapine by activated carbon, establish a method for evaluating the adsorption efficacy of activated carbon on quetiapine, and assess the adsorption effects both in vitro and in vivo.Methods:In vitro experiments involved incubating activated carbon with quetiapine under different conditions, including varying organic solvent contents, types of organic solvents, adsorption temperatures, adsorption times, and pH. After reaching equilibrium, the mixtures were centrifuged, and the supernatants were collected. The concentration of quetiapine in the supernatants was measured using LC-MS/MS, and the adsorption rates were calculated. The log-transformed concentration of activated carbon was used as the independent variable and the adsorption rate as the dependent variable for function fitting using Origin 2021 software. In the in vivo experiments, rats were administered quetiapine orally, followed by 125 mg/mL of activated carbon in the experimental group. Blood samples were collected at multiple time points pre- and post-administration (0.17 h, 0.33 h, 0.50 h, 0.75 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h, and 24 h). Plasma samples were pre-treated and the quetiapine concentrations were determined using LC-MS/MS. Pharmacokinetic parameters for both control and experimental groups were calculated using DAS 2.0 software.Results:The factors such as organic solvent content, type of organic solvent, adsorption temperature, adsorption time, and pH value significantly influenced the adsorption efficiency of quetiapine by activated carbon, leading to the optimization and standardization of the in vitro adsorption methodology. Among the 100 different adsorption function models tested, the Boltzmann function was identified as the most suitable models for describing the adsorption of quetiapine by activated carbon. Pharmacokinetic analysis showed that the experimental group treated with activated carbon exhibited significantly reduced C max and AUC for quetiapine compared to the control group. Conclusion:The results of both in vitro and in vivo experiments demonstrate that activated carbon effectively adsorbs quetiapine, providing a potential method for mitigating quetiapine absorption.

Enamel demineralization, the formation of white spot lesions, is a common issue in clinical orthodontic treatment. The appearance of white spot lesions not only affects the texture and health of dental hard tissues but also impacts the health and aesthetics of teeth after orthodontic treatment. The prevention, diagnosis, and treatment of white spot lesions that occur throughout the orthodontic treatment process involve multiple dental specialties. This expert consensus will focus on providing guiding opinions on the management and prevention of white spot lesions during orthodontic treatment, advocating for proactive prevention, early detection, timely treatment, scientific follow-up, and multidisciplinary management of white spot lesions throughout the orthodontic process, thereby maintaining the dental health of patients during orthodontic treatment.
Humans ; Consensus ; Dental Caries/etiology* ; Dental Enamel/pathology* ; Tooth Demineralization/etiology* ; Tooth Remineralization

Numerous c-mesenchymal-epithelial transition (c-MET) inhibitors have been reported as potential anticancer agents. However, most fail to enter clinical trials owing to poor efficacy or drug resistance. To date, the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed. In this study, we constructed the largest c-MET dataset, which included 2,278 molecules with different structures, by inhibiting the half maximal inhibitory concentration (IC₅₀) of kinase activity. No significant differences in drug-like properties were observed between active molecules (1,228) and inactive molecules (1,050), including chemical space coverage, physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding (t-SNE) high-dimensional data. Further clustering and chemical space networks (CSNs) analyses revealed commonly used scaffolds for c-MET inhibitors, such as M5, M7, and M8. Activity cliffs and structural alerts were used to reveal "dead ends" and "safe bets" for c-MET, as well as dominant structural fragments consisting of pyridazinones, triazoles, and pyrazines. Finally, the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules, including at least three aromatic heterocycles, five aromatic nitrogen atoms, and eight nitrogen-oxygen atoms. Overall, our analyses revealed potential structure-activity relationship (SAR) patterns for c-MET inhibitors, which can inform the screening of new compounds and guide future optimization efforts.