Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
Animals ; ADAM10 Protein/metabolism* ; Alzheimer Disease/pathology* ; Amyloid Precursor Protein Secretases/metabolism* ; Disease Models, Animal ; Humans ; Mice ; Amyloid beta-Peptides/metabolism* ; Male ; Mice, Transgenic ; Membrane Proteins/metabolism* ; Cognitive Dysfunction/pathology* ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/metabolism* ; Female ; Hippocampus/metabolism* ; Long-Term Potentiation/physiology*

Objective:To investigate the risk factors of secondary primary cancer (SPC) after cervical cancer and to construct a nomogram model for predicting the prognosis.Methods:The data of 3 790 patients with primary cervical cancer from the 3rd edition of the International Classification of Diseases Oncology (ICD-O-3) number C53.9 between 2000 and 2020 in the Surveillance, Epidemiology and End Results (SEER) database were retrospectively analyzed, and SPC occurred in 2 036 cases out of 3 790 patients. Standardized incidence rate (SIR) of patients with cervical cancer was calculated by using SEER*Stat software; Cox proportional hazards model was used to make the univariate and multivariate analysis on the influencing factors of the overall survival (OS) in patients with SPC after cervical cancer. By using the "rms" package of R software, nomogram models for predicting 1-, 3-, and 5-year OS rates in SPC patients after cervical cancer were constructed based on prognostic independent influencing factors. The prediction efficacy and consistency of the model were verified by using the receiver operating characteristic (ROC) curve and the calibration curve.Results:The cervical cancer patients with the age of diagnosis of 20-34 years old (SIR: 1.76, 95% CI: 1.57-1.98), black race (SIR: 1.75, 95% CI: 1.61-1.90), the interval period of 2 primary tumors: 6-11 months (SIR: 1.69, 95% CI: 1.50-1.90), histologic grade Ⅳ (SIR: 1.62, 95% CI: 1 30-2.00), chemotherapy (SIR: 1.63, 95% CI: 1.56-1.71), radiotherapy (SIR: 1.59, 95% CI: 1.53-1.66), unmarried (SIR: 1.47, 95% CI: 1.41-1.54) had high SIR. Multivariate Cox regression analysis results of 2 036 SPC patients after cervical cancer showed that unmarried, SEER stage of regional lesion phase, distant metastasis phase and unknown, histologic grade of Ⅱ, Ⅲ, Ⅳ and the unknown, unknown lymph node dissection, other sites expert for lymphoma in SPC sites were independent risk factors of OS in SPC patients after cervical cancer (all P < 0.05); receiving surgery for SPC (compared to those not receiving surgery, HR = 0.38, 95% CI: 0.32-0.45, P = 0.001), radiotherapy (compared to those not receiving radiotherapy or unknown, HR = 0.66, 95% CI: 0.56-0.78, P = 0.001), and chemotherapy (compared to those not receiving chemotherapy or unknown, HR = 0.86, 95% CI:0.74-0.99, P = 0.034) were independent protective factors of OS in SPC patients after cervical cancer. The results of Kaplan-Meier survival analysis showed that the differences in the OS of SPC patients after cervical cancer with different marriage status, SEER stage, histologic grade, lymph node dissection, surgery for SPC, primary sites of SPC and whether receiving radiochemotherapy were all statistically significant (all P < 0.001). Based on the 8 variables including marital status, SEER stage, histologic grade, whether lymph nodes have been cleared, whether SPC has been treated with surgery, radiotherapy, chemotherapy, and the primary sites of SPC, a nomogram model for predicting the 1-, 3- and 5-year OS rates of SPC patients after cervical cancer was established. The results of ROC curve analysis showed that the area under the curve of the model for predicting 1-, 3-, and 5-year OS rates was 0.841, 0.847, and 0.847, respectively. The calibration curves showed a good consistency between the predicted results of model and the actual results. Conclusions:A prognostic prediction nomogram model for SPC after cervical cancer constructed based on the data in the SEER database has a high clinical application value and calibration.

Objective:To investigate the role of YTHDF2 in cervical lesions and its potential molecular mechanism.Methods:Gene expression data of cervical tissue were obtained from the GEO database to analyze the expression of YTHDF2 mRNA and perform pathway enrichment analysis. Patients with cervical lesions diagnosed by thinprep cytologic test in Gynecological Outpatient Department of Maternal and Child Health Hospital in Jiexiu, Shanxi Province, were selected as the research subjects. Data of cervical lesions and cervical exfoliated cells were collected. HPV infection status was detected by flow-through hybridization, and the expression of YTHDF2 mRNA was detected by reverse transcription real-time polymerase chain reaction. The expression of YTHDF2 in cervical lesions and the mediating role of HPV infection in the relationship between YTHDF2 and squamous intraepithelial lesion (SIL) were evaluated. YTHDF2-related genes were screened from multiple datasets in the GEO and ENCORI databases, and their expression, immune infiltration, and survival analysis were performed to assess the association between YTHDF2 and prognosis. Results:Compared with normal cervical tissue, YTHDF2 was highly expressed in cervical lesion tissue ( P<0.05). A total of 3 672 differentially expressed genes were screened from the dataset GSE49339. Gene Ontology analysis showed that YTHDF2 was mainly involved in transcription regulation. Kyoto Encyclopedia of Genes and Genomes analysis showed that YTHDF2 might be related to HPV infection and other signaling pathways. In the mediation analysis, χ2 test results showed that the expression level of YTHDF2 was significantly different among groups ( χ2=22.47, P<0.001). Trend χ2 test further showed that the expression level of YTHDF2 was upregulated with the degree of cervical precancerous lesions (trend χ2=10.26, P=0.001). Multivariate logistic regression analysis indicated that high YTHDF2 expression increased the risk of low-grade squamous intraepithelial lesions ( OR=3.15, 95% CI: 1.93-5.15) and high-grade squamous intraepithelial lesions ( OR=1.85, 95% CI: 1.01-3.39). Mediation effect analysis revealed a partial mediating effect of HPV infection between YTHDF2 and SIL, accounting for 32.02% of the total effect. Twelve YTHDF2 related genes were screened by the intersection of multiple datasets. The immune infiltration analysis results showed that YTHDF2 and related genes KLF4, E2F3 and HOXC6 were associated with immune infiltration (all P<0.05). Multivariate Cox proportional hazard regression model analysis showed that low expression of KLF4 ( HR=0.53, 95% CI: 0.30-0.94) and high expression of RHOB ( HR=1.80, 95% CI: 1.04-3.13) were risk factors for the prognosis of cervical cancer. Conclusion:YTHDF2 is highly expressed in cervical lesions and may have been involved in the regulation of HPV infection-related pathways and its downstream related genes are related to immune infiltration and prognosis of cervical cancer, providing a theoretical basis for the study of mechanisms related to cervical lesions.

Objective:To investigate the impact of chromate exposure on pulmonary function indices in occupational populations and explore the potential role of alterations in inflammatory indicators in this process.Methods:In July 2024, A cross-sectional analysis was conducted using occupational health examination data of 30875 workers from chromate-related enterprises in Jiangsu Province in 2020 and 2021. Based on the occupational positions and whether there is chromium acid salt exposure in the occupational hazards of the research subjects over the years, they are divided into chromium acid salt exposure group and non-exposure group. For those exposed to chromium acid salts, based on job position descriptions and duration of chromium acid salt exposure, they are further categorized into intermittent exposure group and continuous exposure group; among them, the actual exposure time in the intermittent exposure group is less than half of the working shift time, and the exposure duration is less than the total working life. Pulmonary function test indicators include forced vital capacity (forced vital capacity, FVC) %, first-second forced expiratory volume (forced expiratory volume in one second, FEV 1.0) %, and the ratio of first-second forced expiratory volume to forced vital capacity (FEV 1.0/FVC) %. Peripheral blood samples from the upper limbs of the research subjects were collected on an empty stomach for routine blood tests, selecting neutrophil count, platelet count, and lymphocyte count results, calculating the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Quantitative data that meet normal distribution are expressed using Mean±SD, while variables that do not meet normal distribution are represented by M ( Q1, Q3). Categorical data are expressed using frequency or proportion (%). Linear variable comparisons between groups use t-tests. Generalized linear models were employed to assess the correlation between chromate exposure and pulmonary function indices, while mixed regression models were utilized to explore potential underlying effects. Results:Compared with the non-exposed group, the pulmonary function indices FVC (%), FEV 1.0/FVC (%), and FEV 1.0 (%) in the chromate-exposed group showed a decreasing trend ( P<0.01), indicating statistically significant differences. As the frequency of chromate exposure increased, the prevalence of pulmonary dysfunction rose. The prevalence rates of obstructive, restrictive, and mixed respiratory dysfunction among the chromate-exposed population (including intermittent exposure and continuous exposure groups) were 0.26%, 4.67%, and 0.12%, which were higher than those in the non-exposed group (0.09%, 0.84%, and 0.07%, respectively). All these differences were statistically significant ( P<0.05). After stratification by gender, a negative correlation was observed between chromate exposure and the inflammatory indicator platelet-to-lymphocyte ratio (PLR) ( P<0.05). Potential effect analysis revealed that PLR played a certain mediating role between chromate exposure and the decline in pulmonary function indices, with a mediating proportion of 2.2%. Conclusion:Chromate exposure in occupational populations may lead to a decline in pulmonary ventilatory function and alterations in peripheral blood inflammatory indicators. Inflammatory indicators may be involved in the pulmonary function decline caused by chromate exposure.

Objective:To investigate the role of YTHDF2 in cervical lesions and its potential molecular mechanism.Methods:Gene expression data of cervical tissue were obtained from the GEO database to analyze the expression of YTHDF2 mRNA and perform pathway enrichment analysis. Patients with cervical lesions diagnosed by thinprep cytologic test in Gynecological Outpatient Department of Maternal and Child Health Hospital in Jiexiu, Shanxi Province, were selected as the research subjects. Data of cervical lesions and cervical exfoliated cells were collected. HPV infection status was detected by flow-through hybridization, and the expression of YTHDF2 mRNA was detected by reverse transcription real-time polymerase chain reaction. The expression of YTHDF2 in cervical lesions and the mediating role of HPV infection in the relationship between YTHDF2 and squamous intraepithelial lesion (SIL) were evaluated. YTHDF2-related genes were screened from multiple datasets in the GEO and ENCORI databases, and their expression, immune infiltration, and survival analysis were performed to assess the association between YTHDF2 and prognosis. Results:Compared with normal cervical tissue, YTHDF2 was highly expressed in cervical lesion tissue ( P<0.05). A total of 3 672 differentially expressed genes were screened from the dataset GSE49339. Gene Ontology analysis showed that YTHDF2 was mainly involved in transcription regulation. Kyoto Encyclopedia of Genes and Genomes analysis showed that YTHDF2 might be related to HPV infection and other signaling pathways. In the mediation analysis, χ2 test results showed that the expression level of YTHDF2 was significantly different among groups ( χ2=22.47, P<0.001). Trend χ2 test further showed that the expression level of YTHDF2 was upregulated with the degree of cervical precancerous lesions (trend χ2=10.26, P=0.001). Multivariate logistic regression analysis indicated that high YTHDF2 expression increased the risk of low-grade squamous intraepithelial lesions ( OR=3.15, 95% CI: 1.93-5.15) and high-grade squamous intraepithelial lesions ( OR=1.85, 95% CI: 1.01-3.39). Mediation effect analysis revealed a partial mediating effect of HPV infection between YTHDF2 and SIL, accounting for 32.02% of the total effect. Twelve YTHDF2 related genes were screened by the intersection of multiple datasets. The immune infiltration analysis results showed that YTHDF2 and related genes KLF4, E2F3 and HOXC6 were associated with immune infiltration (all P<0.05). Multivariate Cox proportional hazard regression model analysis showed that low expression of KLF4 ( HR=0.53, 95% CI: 0.30-0.94) and high expression of RHOB ( HR=1.80, 95% CI: 1.04-3.13) were risk factors for the prognosis of cervical cancer. Conclusion:YTHDF2 is highly expressed in cervical lesions and may have been involved in the regulation of HPV infection-related pathways and its downstream related genes are related to immune infiltration and prognosis of cervical cancer, providing a theoretical basis for the study of mechanisms related to cervical lesions.

Objective:To investigate the risk factors of secondary primary cancer (SPC) after cervical cancer and to construct a nomogram model for predicting the prognosis.Methods:The data of 3 790 patients with primary cervical cancer from the 3rd edition of the International Classification of Diseases Oncology (ICD-O-3) number C53.9 between 2000 and 2020 in the Surveillance, Epidemiology and End Results (SEER) database were retrospectively analyzed, and SPC occurred in 2 036 cases out of 3 790 patients. Standardized incidence rate (SIR) of patients with cervical cancer was calculated by using SEER*Stat software; Cox proportional hazards model was used to make the univariate and multivariate analysis on the influencing factors of the overall survival (OS) in patients with SPC after cervical cancer. By using the "rms" package of R software, nomogram models for predicting 1-, 3-, and 5-year OS rates in SPC patients after cervical cancer were constructed based on prognostic independent influencing factors. The prediction efficacy and consistency of the model were verified by using the receiver operating characteristic (ROC) curve and the calibration curve.Results:The cervical cancer patients with the age of diagnosis of 20-34 years old (SIR: 1.76, 95% CI: 1.57-1.98), black race (SIR: 1.75, 95% CI: 1.61-1.90), the interval period of 2 primary tumors: 6-11 months (SIR: 1.69, 95% CI: 1.50-1.90), histologic grade Ⅳ (SIR: 1.62, 95% CI: 1 30-2.00), chemotherapy (SIR: 1.63, 95% CI: 1.56-1.71), radiotherapy (SIR: 1.59, 95% CI: 1.53-1.66), unmarried (SIR: 1.47, 95% CI: 1.41-1.54) had high SIR. Multivariate Cox regression analysis results of 2 036 SPC patients after cervical cancer showed that unmarried, SEER stage of regional lesion phase, distant metastasis phase and unknown, histologic grade of Ⅱ, Ⅲ, Ⅳ and the unknown, unknown lymph node dissection, other sites expert for lymphoma in SPC sites were independent risk factors of OS in SPC patients after cervical cancer (all P < 0.05); receiving surgery for SPC (compared to those not receiving surgery, HR = 0.38, 95% CI: 0.32-0.45, P = 0.001), radiotherapy (compared to those not receiving radiotherapy or unknown, HR = 0.66, 95% CI: 0.56-0.78, P = 0.001), and chemotherapy (compared to those not receiving chemotherapy or unknown, HR = 0.86, 95% CI:0.74-0.99, P = 0.034) were independent protective factors of OS in SPC patients after cervical cancer. The results of Kaplan-Meier survival analysis showed that the differences in the OS of SPC patients after cervical cancer with different marriage status, SEER stage, histologic grade, lymph node dissection, surgery for SPC, primary sites of SPC and whether receiving radiochemotherapy were all statistically significant (all P < 0.001). Based on the 8 variables including marital status, SEER stage, histologic grade, whether lymph nodes have been cleared, whether SPC has been treated with surgery, radiotherapy, chemotherapy, and the primary sites of SPC, a nomogram model for predicting the 1-, 3- and 5-year OS rates of SPC patients after cervical cancer was established. The results of ROC curve analysis showed that the area under the curve of the model for predicting 1-, 3-, and 5-year OS rates was 0.841, 0.847, and 0.847, respectively. The calibration curves showed a good consistency between the predicted results of model and the actual results. Conclusions:A prognostic prediction nomogram model for SPC after cervical cancer constructed based on the data in the SEER database has a high clinical application value and calibration.

Objective:To investigate the impact of chromate exposure on pulmonary function indices in occupational populations and explore the potential role of alterations in inflammatory indicators in this process.Methods:In July 2024, A cross-sectional analysis was conducted using occupational health examination data of 30875 workers from chromate-related enterprises in Jiangsu Province in 2020 and 2021. Based on the occupational positions and whether there is chromium acid salt exposure in the occupational hazards of the research subjects over the years, they are divided into chromium acid salt exposure group and non-exposure group. For those exposed to chromium acid salts, based on job position descriptions and duration of chromium acid salt exposure, they are further categorized into intermittent exposure group and continuous exposure group; among them, the actual exposure time in the intermittent exposure group is less than half of the working shift time, and the exposure duration is less than the total working life. Pulmonary function test indicators include forced vital capacity (forced vital capacity, FVC) %, first-second forced expiratory volume (forced expiratory volume in one second, FEV 1.0) %, and the ratio of first-second forced expiratory volume to forced vital capacity (FEV 1.0/FVC) %. Peripheral blood samples from the upper limbs of the research subjects were collected on an empty stomach for routine blood tests, selecting neutrophil count, platelet count, and lymphocyte count results, calculating the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Quantitative data that meet normal distribution are expressed using Mean±SD, while variables that do not meet normal distribution are represented by M ( Q1, Q3). Categorical data are expressed using frequency or proportion (%). Linear variable comparisons between groups use t-tests. Generalized linear models were employed to assess the correlation between chromate exposure and pulmonary function indices, while mixed regression models were utilized to explore potential underlying effects. Results:Compared with the non-exposed group, the pulmonary function indices FVC (%), FEV 1.0/FVC (%), and FEV 1.0 (%) in the chromate-exposed group showed a decreasing trend ( P<0.01), indicating statistically significant differences. As the frequency of chromate exposure increased, the prevalence of pulmonary dysfunction rose. The prevalence rates of obstructive, restrictive, and mixed respiratory dysfunction among the chromate-exposed population (including intermittent exposure and continuous exposure groups) were 0.26%, 4.67%, and 0.12%, which were higher than those in the non-exposed group (0.09%, 0.84%, and 0.07%, respectively). All these differences were statistically significant ( P<0.05). After stratification by gender, a negative correlation was observed between chromate exposure and the inflammatory indicator platelet-to-lymphocyte ratio (PLR) ( P<0.05). Potential effect analysis revealed that PLR played a certain mediating role between chromate exposure and the decline in pulmonary function indices, with a mediating proportion of 2.2%. Conclusion:Chromate exposure in occupational populations may lead to a decline in pulmonary ventilatory function and alterations in peripheral blood inflammatory indicators. Inflammatory indicators may be involved in the pulmonary function decline caused by chromate exposure.

Improving the entire outpatient clinic experience is an important measure in the new era to enhance patients'sense of gain from medical treatment.Beijing Tongren Hospital Affiliated to Capital Medical University explores the establishment of a full-process outpatient service management system based on continuous improvement of medical services.Through the concept of forward service,it focuses on the patient's pre-diagnosis experience;the process is simplified and intelligently guided to optimize the patient's in-diagnosis experience;and continuous diagnosis and treatment Model innovation improves patients'post-diagnosis experience and creates a Chinese-style modern outpatient medical service model to continuously meet the people's growing needs for a better life.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2A^APP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

Improving the entire outpatient clinic experience is an important measure in the new era to enhance patients'sense of gain from medical treatment.Beijing Tongren Hospital Affiliated to Capital Medical University explores the establishment of a full-process outpatient service management system based on continuous improvement of medical services.Through the concept of forward service,it focuses on the patient's pre-diagnosis experience;the process is simplified and intelligently guided to optimize the patient's in-diagnosis experience;and continuous diagnosis and treatment Model innovation improves patients'post-diagnosis experience and creates a Chinese-style modern outpatient medical service model to continuously meet the people's growing needs for a better life.