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.

OBJECTIVE: Lipid oxidation is involved in the pathogenesis of atherosclerosis and may be contribute to the development of Ischemic stroke (IS). However, the lipid profiles associated with IS have been poorly studied. We conducted a pilot study to identify potential IS-related lipid molecules and pathways using lipidomic profiling. METHODS: Serum lipidomic profiling was performed using LC-MS in 20 patients with IS and 20 age- and sex-matched healthy controls. Univariate and multivariate analyses were simultaneously performed to identify the differential lipids. Multiple testing was controlled for using a false discovery rate (FDR) approach. Enrichment analysis was performed using MetaboAnalyst software. RESULTS: Based on the 294 lipids assayed, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models were used to distinguish patients with IS from healthy controls. Fifty-six differential lipids were identified with an FDR-adjusted P less than 0.05 and variable influences in projection (VIP) greater than 1.0. These lipids were significantly enriched in glycerophospholipid metabolism (FDR-adjusted P = 0.009, impact score = 0.216). CONCLUSIONS Serum lipid profiles differed significantly between patients with IS and healthy controls. Thus, glycerophospholipid metabolism may be involved in the development of IS. These results provide initial evidence that lipid molecules and their related metabolites may serve as new biomarkers and potential therapeutic targets for IS.
Humans ; Pilot Projects ; Lipidomics ; Male ; Female ; Biomarkers/blood* ; Middle Aged ; Ischemic Stroke/blood* ; Aged ; China ; Lipids/blood* ; Adult ; Case-Control Studies ; East Asian People

OBJECTIVE: To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease. METHODS: This prospective cohort study included 318,085 biobank participants from the UK. Physical activity was assessed using the short form of the International Physical Activity Questionnaire. The participants were stratified into low-, intermediate-, and high-genetic-risk groups based on their polygenic risk scores. Multivariate Cox regression models and multiplicative interaction analyses were used. RESULTS: During a median follow-up period of 13 years, 9,209 participants were diagnosed with chronic obstructive pulmonary disease. For low genetic risk, compared to low physical activity, the hazard ratios ( HRs) for moderate and high physical activity were 0.853 (95% confidence interval [ CI]: 0.748-0.972) and 0.831 (95% CI: 0.727-0.950), respectively. For intermediate genetic risk, the HRs were 0.829 (95% CI: 0.758-0.905) and 0.835 (95% CI: 0.764-0.914), respectively. For participants with high genetic risk, the HRs were 0.809 (95% CI: 0.746-0.877) and 0.818 (95% CI: 0.754-0.888), respectively. A significant interaction was observed between genetic risk and physical activity. CONCLUSION Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups, highlighting the need to tailor activity interventions for genetically susceptible individuals.
Humans ; Pulmonary Disease, Chronic Obstructive/epidemiology* ; Exercise ; Male ; Female ; Middle Aged ; Prospective Studies ; Aged ; Genetic Predisposition to Disease ; Risk Factors ; United Kingdom/epidemiology* ; Incidence ; Adult

Objective: To investigate the basic situation of pre-analytical quality management in blood station laboratories in North China, and to provide baseline data for promoting the homogenization and standardization of these pre-analytical processes in each blood station laboratory. Methods: A cross-sectional status survey was designed based on the quality management regulations of blood stations, ISO15189 standards and relevant quality management requirements. This survey covering various aspects including laboratory general situation, sample collection and temporary storage, transportation, reception, and quality continuous improvement situations. Data analysis was performed on the survey results of each laboratory. Results: All the 38 blood station laboratories in North China had established a pre-analytical quality management system framework and implemented basic pre-analytical quality control activities; however, there were differences in implementation. 1) Among the 12 basic quality items, 3 items were monitored by all the investigated laboratories (100%), 6 items were monitored by the vast majority of laboratories (about 90%), and 3 items were monitored by a portion of laboratories (about 60%). There were no significant differences in the monitoring index among the three regions and among different types of laboratories (P>0.05). 2) Among the total of 26 items in the three key processes before testing (sample collection and storage, transportation, reception and processing), 12 items were monitored by all laboratories (100%), 11 items were monitored by the vast majority of laboratories (about 90%), and 3 items were monitored by a portion of laboratories (about 75%). There were no significant differences in monitoring index among different regions and types of laboratories (P>0.05). Conclusion: This survey provides a reference and basis for the gap analysis of the pre-analytical process quality management in 38 blood station laboratories across North China. It facilitates laboratories in identifying pre-analytical quality problems, resolving problems, preventing errors, and ensuring that the quality of blood samples before testing meets the established requirements. It lays a foundation for the homogenization of pre-analytical quality management in regional blood stations.

Objective: To determine the frequency and main reasons of unqualified samples by analyzing the quality of pre-analytical samples in blood stations in North China, thereby providing a reference and basis for gap analysis in the implementation of pre-analytical process quality management for participating laboratories and ensuring that only high-standard and high-quality blood samples proceed to testing. Methods: Data on the quality of pre-analytical samples from blood station laboratories in North China was collected via questionnaire. Statistical analysis were performed on: 1) the basic information of samples quality monitoring in the laboratories; 2) the distribution of the overall pre-analytical unqualified rate of samples and the pre-analytical unqualified rate of samples in each laboratory; 3) the distribution of reasons for sample disqualification. Results: 1) The overall pre-analytical unqualified rate of samples in blood station laboratories in North China was 4.55, with a total sigma level of 5.39σ. The 25th, 50th and 75th percentiles (P25, P50, P75) for the total unqualified rate were 0.00, 1.10 and 5.96, respectively. The corresponding percentiles for the Sigma level were 5.34σ, 5.71σ, and 6.00σ, respectively. The pre-analytical unqualified rate of serological and nucleic acid samples (4.89 vs 4.22) showed a significant difference (χ =9.575, P<0.05). 2) The average unqualified rate of samples in region A, B and C was 1.71, 9.50 and 12.64 (χ =1 590.721, P<0.05), and the sigma level was 5.66σ, 5.21σ and 5.16σ, respectively. 3) The main reasons for unqualified serological samples were chylous blood (72.65%), hemolysis (17.39%), abnormal hematocrit (5.80%), and insufficient volume (3.50%). The main reasons for the unqualified nucleic acid samples were chylous blood (78.26%), hemolysis (8.84%), failure to centrifuge as required (5.01%), abnormal hematocrit (4.66%), and insufficient volume (1.92%). Conclusion: In North China, the quality indicators for the pre-analytical processes in blood station laboratories are generally well-managed. Laboratories in region A outperformed the national average in pre-analytical specimen quality control. However, participating laboratories exhibit gaps in implementing pre-analytical quality management. Through effective analysis of pre-analytical process quality metrics and inter-laboratory comparisons, laboratories can identify discrepancies and address shortcomings. By establishing clear quality objectives, they can achieve continuous improvement and ensure the validity of test results.

Objective: To investigate the assessment criteria and subsequent handling practices of hemolytic and lipemic blood samples before testing in blood screening laboratories in North China, and to provide data to support the standardization of their management in blood station laboratories. Methods: Data on the preanalytical management of hemolytic and lipemic samples from 38 laboratories were collected. The details of management on the criteria and verificatioon for assessment, the assessment methods, and subsequent handling procedures of hemolytic and lipemic samples in blood station laboratories were analyzed. Results: 1) All 38 blood station laboratories monitored serological and nucleic acid samples for hemolysis and lipemia in pre-analytical phase. 2) The criteria and methods for assessing hemolytic and lipemic samples varied among the laboratories of the 38 blood stations. 15 laboratories (39.47%) followed manufacturer's instructions, 9 laboratories (23.68%) formulated their own criteria, and 14 laboratories (36.84%) referred to the criteria of other laboratories. 16 laboratories (42.11%) verified the criteria for assessing hemolytic and lipemic samples, with significant variations in verification rate across laboratories from different regions (P<0.05). For the assessment methods, visual inspection was used by 28 laboratories (73.68%) for hemolytic samples and by 27 laboratories (71.05%) for lipemic samples; the colorimetric card method was used by 10 laboratories (26.32%) for assessing both hemolytic and lipemic samples; the instrumental method was used by 1 laboratory (2.63%) for assessing lipemic samples.3) The handling procedures for hemolytic and lipemic samples varied significantly and followed a gradient distribution pattern among 38 laboratories (including accepting samples for testing, accepting samples for concession testing, re-collecting samples, and rejecting samples and halting testing). With increasing severity of hemolysis and lipemia, more laboratories halted testing, and relatively fewer laboratories accepted samples for normal testing. 5 laboratories (13.16%) applied different handling procedures on serological and nucleic acid samples. Conclusion: This survey provides a reference and basis for analyzing gaps in the management of hemolytic and lipemic samples during the preanalyical phase in blood station laboratories in North China. It enables laboratories to identify the problems and deficiencies in the management of hemolytic and lipemic samples, to ensure preanalytical samples quality meets the established requirements, and to lay a foundation for promoting the homogenization and standardization of the regional sample quality management mode.

Purpose: This study aimed to evaluate the contrast-enhanced ultrasound with Sonazoid (Sonazoid-CEUS) features of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). Methods: In this retrospective study, patients who underwent surgical resection and were histopathologically diagnosed with NAFLD or cirrhosis-related HCC were included. All patients received Sonazoid-CEUS examinations within 1 week prior to hepatic surgery. The enhancement patterns of HCC lesions were evaluated and compared between the two groups according to the current World Federation for Ultrasound in Medicine and Biology guidelines. Multivariate logistic regression analysis was used to assess the correlations between Sonazoid-CEUS enhancement patterns and clinicopathologic characteristics. Results: From March 2022 to April 2023, a total of 151 patients with HCC were included, comprising 72 with NAFLD-related HCC and 79 with hepatitis B virus (HBV) cirrhosis–related HCC. On Sonazoid-CEUS, more than half of the NAFLD-related HCCs exhibited relatively early and mild washout within 60 seconds (54.2%, 39/72), whereas most HBV cirrhosis–related HCCs displayed washout between 60 and 120 seconds (46.8%, 37/79) or after 120 seconds (39.2%, 31/79) (P<0.001). In the patients with NAFLD-related HCC, multivariate analysis revealed that international normalized ratio (odds ratio [OR], 0.002; 95% confidence interval [CI], 0.000 to 0.899; P=0.046) and poor tumor differentiation (OR, 21.930; 95% CI, 1.960 to 245.319; P=0.012) were significantly associated with washout occurring within 60 seconds. Conclusion Characteristic Sonazoid-CEUS features are useful for diagnosing HCC in patients with NAFLD.

Male factors contribute to 50% of infertility cases, with 20%-30% of cases being solely attributed to male infertility. Helicase for meiosis 1 ( HFM1 ) plays a crucial role in ensuring proper crossover formation and synapsis of homologous chromosomes during meiosis, an essential process in gametogenesis. HFM1 gene mutations are associated with male infertility, particularly in cases of non-obstructive azoospermia and severe oligozoospermia. However, the effects of intracytoplasmic sperm injection (ICSI) in HFM1 -related infertility cases remain inadequately explored. This study identified novel biallelic HFM1 variants through whole-exome sequencing (WES) in a Chinese patient with severe oligozoospermia, which was confirmed by Sanger sequencing. The pathogenicity of these variants was assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunoblotting, which revealed a significant reduction in HFM1 mRNA and protein levels in spermatozoa compared to those in a healthy control. Transmission electron microscopy revealed morphological abnormalities in sperm cells, including defects in the head and flagellum. Despite these abnormalities, ICSI treatment resulted in a favorable fertility outcome for the patient, indicating that assisted reproductive techniques (ART) can be effective in managing HFM1 -related male infertility. These findings offer valuable insights into the management of such cases.
Humans ; Male ; Sperm Injections, Intracytoplasmic ; Oligospermia/therapy* ; Adult ; Spermatozoa/ultrastructure* ; Exome Sequencing ; Mutation

OBJECTIVES: To explore the application of the colloidal gold method and chemiluminescence method in detecting gonadotropin (Gn) in morning urine for assessing pubertal development status in children. METHODS: A total of 132 children diagnosed with central precocious puberty (CPP), early and fast puberty (EFP), and premature thelarche (PT) at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from November 2021 to December 2022 were included, along with 685 healthy children who underwent routine health examinations at the hospital's pediatric health care department during the same period. All 132 patients underwent a gonadotropin-releasing hormone (GnRH) stimulation test. Both patients and healthy children had their urinary Gn levels measured using the colloidal gold method and chemiluminescence method, including levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The correlation between serum Gn and urinary Gn detected by the two methods, as well as the correlation between Tanner stages of healthy children and urinary Gn, was analyzed. RESULTS: Urine Gn levels detected by both the colloidal gold method and chemiluminescence method showed a positive correlation with serum LH baseline values, LH peak values, baseline LH/FSH ratios, and peak LH/FSH ratios (P<0.05). In healthy children, urinary LH levels detected by the chemiluminescence method gradually increased from Tanner stage Ⅰ to Ⅳ (P<0.05), while urinary FSH levels were lower in Tanner stage I than in stages Ⅱ, Ⅲ, and IV (P<0.05). Urinary LH levels detected by the colloidal gold method were lower in Tanner stage I compared to stages Ⅱ, Ⅲ, and IV, with the highest levels observed in Tanner stage Ⅳ (P<0.05). Additionally, urinary FSH levels in Tanner stage Ⅲ were higher than in stages Ⅰ and Ⅱ (P<0.05). The area under the receiver operating characteristic curve for evaluating Tanner stages I and II in healthy children using urinary LH and FSH levels by the chemiluminescence method and urinary LH levels by the colloidal gold method were 0.730, 0.699, and 0.783, respectively. CONCLUSIONS The colloidal gold method and chemiluminescence method for detecting Gn in morning urine show good correlation with serum Gn levels. As a non-invasive and convenient detection method, the colloidal gold method can serve as a useful tool for screening the onset of pubertal development in children.
Humans ; Child ; Male ; Female ; Gold Colloid ; Luminescent Measurements/methods* ; Gonadotropins/urine* ; Puberty ; Luteinizing Hormone/urine* ; Child, Preschool ; Adolescent ; Follicle Stimulating Hormone/urine*