Background:To compare the efficacy and safety of monthly administrations of gonadotropin releasing hormone (GnRH) agonists LY01005 and Zoladex ? in Chinese patients with premenopausal breast cancer. Methods:From October 2020 to November 2021, 188 premenopausal breast cancer patients were enrolled in 34 hospitals and randomized 1:1 to receive either LY01005 or Zoladex ? every 28 days for a total of three injections. All patients concomitantly received oral tamoxifen (TAM). The primary efficacy endpoint was cumulative probability of maintaining menopausal level [oestradiol (E2) ≤30 pg/ml] from day 29 to day 85. The second efficacy endpoint included changes in E2, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared with the baseline. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were analyzed. The study also evaluated the pharmacokinetic and pharmacodynamic characteristics of LY01005. Results:A total of 188 patients were randomised and 187 patients received either LY01005 or Zoladex ?. Cumulative probabilities of maintaining menopausal level (E2≤30 pg/ml) from day 29 to day 85 were 93.1% for LY01005 and 86.3% for Zoladex ?. The between-group difference was 6.8% (95% CI: -2.3%, 15.9%) and primary efficacy in the LY01005 group was not inferior to that in the Zoladex ? group. Changes in E2, LH, and FSH levels compared with the baseline were equivalent between the two groups (E2: 89.34% to 90.23% vs. 82.11% to 85.02%; LH: 88.89% to 95.52% vs. 89.70% to 97.02%; FSH: 75.36% to 80.85% vs.73.07% to 80.24%, respectively). After three consecutive doses of LY01005, the LH and FSH levels of the subjects showed a transient increase after the first dose, reached a peak on the second day and then started to decrease. The LH and FSH reached a lower level and remained at or below that level until the 85th day. Both treatments were well-tolerated. Conclusion:LY01005 is as effective as Zoladex ? in suppressing E2 to menopausal levels in Chinese patients with premenopausal breast cancer, with a similar safety profile.

This study aims to investigate the changes in blood biochemical indicators of tongue roll-ing(TR)behavior in cattle and their correlation with changes in oral microbiota,laying a founda-tion for further exploring the relationship between animal oral microbiota,biochemical indicators,and behavioral changes.It also provides theoretical basis for preventing and treating TR behavior through regulating oral microbiota.This study intends to analyze and compare the blood biochemi-cal indicators and changes in oral microbiota of cattle with TR behavior and healthy cattle without TR behavior(healthy control,H),in order to explore the blood biochemical indicators of TR cattle and their correlation with changes in oral microbiota.Blood samples from the caudal vein of cattle in each group were collected for the detection of blood biochemical indicators and stress-related hormone indicators.Oral swabs from cattle in each group were collected for 16S rRNA gene se-quencing to analyze the composition,structure,and functional changes of their oral microbiota.The results of blood biochemical indicators in H and TR groups showed that the concentrations of al-bumin(ALB),aspartate aminotransferase(AST),calcium ion(Ca2+),and cortisol in TR group were significantly higher than those in H group(P＜0.05).There were significant differences in beta diversity of oral microbiota between TR and H groups(P＜0.05).At the genus level,the rela-tive abundances of Pseudomonas,Enterobacter,Xanthomonas,and other genera in the oral micro-biota of TR group were significantly higher than those in H group(P＜0.05).However,the rela-tive abundances of Tessaracoccus,Turicibacter,Monoglobus,Dietzia,Bifidobacterium,and other genera in the oral microbiota of TR group were significantly lower than those in H group(P＜0.05).In the KEGG metabolic pathway at the third level,the relative abundances of thiamine me-tabolism,lipoate metabolism,cysteine and methionine metabolism in the oral microbiota of TR group were significantly lower than those in H group(P＜0.05).Spearman correlation analysis showed that ALB and AST were significantly positively correlated with the relative abundances of Pseudomonas and Stenotrophomonas.Therelative abundances of Pseudomonas,Stenotrophomonas,and Sphingomonas were significantly positively correlated with fatty acid metabolism,phosphate and phosphonate metabolism,and lipoate metabolism.ALB was significantly positively correlated with inositol phosphate metabolism and phosphate and phosphonate metabolism.The study found that there were significant differences in blood biochemical indicators and oral microbiota between TR and H groups.In addition,there is a certain correlation between the composition,structure,and function of oral microbiota and the biochemical function of the host.This indicates that TR behav-ior may be associated with changes in the biochemical indicators of the host and the composition,structure,and function of oral microbiota.

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

This study aims to investigate the changes in blood biochemical indicators of tongue roll-ing(TR)behavior in cattle and their correlation with changes in oral microbiota,laying a founda-tion for further exploring the relationship between animal oral microbiota,biochemical indicators,and behavioral changes.It also provides theoretical basis for preventing and treating TR behavior through regulating oral microbiota.This study intends to analyze and compare the blood biochemi-cal indicators and changes in oral microbiota of cattle with TR behavior and healthy cattle without TR behavior(healthy control,H),in order to explore the blood biochemical indicators of TR cattle and their correlation with changes in oral microbiota.Blood samples from the caudal vein of cattle in each group were collected for the detection of blood biochemical indicators and stress-related hormone indicators.Oral swabs from cattle in each group were collected for 16S rRNA gene se-quencing to analyze the composition,structure,and functional changes of their oral microbiota.The results of blood biochemical indicators in H and TR groups showed that the concentrations of al-bumin(ALB),aspartate aminotransferase(AST),calcium ion(Ca2+),and cortisol in TR group were significantly higher than those in H group(P＜0.05).There were significant differences in beta diversity of oral microbiota between TR and H groups(P＜0.05).At the genus level,the rela-tive abundances of Pseudomonas,Enterobacter,Xanthomonas,and other genera in the oral micro-biota of TR group were significantly higher than those in H group(P＜0.05).However,the rela-tive abundances of Tessaracoccus,Turicibacter,Monoglobus,Dietzia,Bifidobacterium,and other genera in the oral microbiota of TR group were significantly lower than those in H group(P＜0.05).In the KEGG metabolic pathway at the third level,the relative abundances of thiamine me-tabolism,lipoate metabolism,cysteine and methionine metabolism in the oral microbiota of TR group were significantly lower than those in H group(P＜0.05).Spearman correlation analysis showed that ALB and AST were significantly positively correlated with the relative abundances of Pseudomonas and Stenotrophomonas.Therelative abundances of Pseudomonas,Stenotrophomonas,and Sphingomonas were significantly positively correlated with fatty acid metabolism,phosphate and phosphonate metabolism,and lipoate metabolism.ALB was significantly positively correlated with inositol phosphate metabolism and phosphate and phosphonate metabolism.The study found that there were significant differences in blood biochemical indicators and oral microbiota between TR and H groups.In addition,there is a certain correlation between the composition,structure,and function of oral microbiota and the biochemical function of the host.This indicates that TR behav-ior may be associated with changes in the biochemical indicators of the host and the composition,structure,and function of oral microbiota.

Background:To compare the efficacy and safety of monthly administrations of gonadotropin releasing hormone (GnRH) agonists LY01005 and Zoladex ? in Chinese patients with premenopausal breast cancer. Methods:From October 2020 to November 2021, 188 premenopausal breast cancer patients were enrolled in 34 hospitals and randomized 1:1 to receive either LY01005 or Zoladex ? every 28 days for a total of three injections. All patients concomitantly received oral tamoxifen (TAM). The primary efficacy endpoint was cumulative probability of maintaining menopausal level [oestradiol (E2) ≤30 pg/ml] from day 29 to day 85. The second efficacy endpoint included changes in E2, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared with the baseline. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were analyzed. The study also evaluated the pharmacokinetic and pharmacodynamic characteristics of LY01005. Results:A total of 188 patients were randomised and 187 patients received either LY01005 or Zoladex ?. Cumulative probabilities of maintaining menopausal level (E2≤30 pg/ml) from day 29 to day 85 were 93.1% for LY01005 and 86.3% for Zoladex ?. The between-group difference was 6.8% (95% CI: -2.3%, 15.9%) and primary efficacy in the LY01005 group was not inferior to that in the Zoladex ? group. Changes in E2, LH, and FSH levels compared with the baseline were equivalent between the two groups (E2: 89.34% to 90.23% vs. 82.11% to 85.02%; LH: 88.89% to 95.52% vs. 89.70% to 97.02%; FSH: 75.36% to 80.85% vs.73.07% to 80.24%, respectively). After three consecutive doses of LY01005, the LH and FSH levels of the subjects showed a transient increase after the first dose, reached a peak on the second day and then started to decrease. The LH and FSH reached a lower level and remained at or below that level until the 85th day. Both treatments were well-tolerated. Conclusion:LY01005 is as effective as Zoladex ? in suppressing E2 to menopausal levels in Chinese patients with premenopausal breast cancer, with a similar safety profile.

With the process of China’s aging population intensifying， palliative care， as an important guarantee for improving the quality of life of terminally ill patients， is receiving more and more social attention， and the demand is constantly increasing. Palliative care needs versatile professionals， and general education can enhance people’s awareness and understanding of it， enabling more people to understand， accept， and participate in palliative care. With the advancement of knowledge and technology in palliative care， the traditional cramming education models are no longer able to meet the actual needs. Therefore， there is an urgent need to innovate palliative care education strategies. By analyzing the current problems in the general education of palliative care in China， this paper proposed thoughts and suggestions for general and innovative education of palliative care in several aspects， such as establishing general and innovative education systems and evaluation systems of palliative care， diversifying educational contents and methods， strengthening medical staffs training， promoting diversified student groups， and strengthening the popularization of palliative care knowledge among the public.

Fifteen compounds were isolated from the 95% ethanol extract of the whole plant of Elephantopus tomentosus L. by silica gel column chromatography, Sephadex LH-20 column chromatography, MCI column chromatography and semi-preparative HPLC methods. Their structures were identified on the basis of physicochemical properties, and spectral data (UV, IR, NMR, MS and CD) analysis as tomenlephanlide A (1), molephantinin (2), molephantin (3), 8-O-methacryloylelephanpane (4), apigenin (5), tricin (6), 2-phenyl acetamide (7), 3,4-dihydroxybenzoic acid methyl ester (8), caffeic acid methyl ester (9), caffeic acid ethyl ester (10), (+)-(4S)-(2E)-4-hydroxy-2-nonenoic acid (11), E-4-hydroxyhex-2-enoic acid (12), 1H-indole-3-carboxylic acid (13), 1H-indole-3-carbaldehyde (14) and isohematinic acid (15). Among them, compound 1 is a new germacrene-type sesquiterpenoid, 5-15 were obtained from E. tomentosus L. for the first time. It was the first time the absolute configuration of compound 2 was reported. Compound 1 showed weak cytotoxicity against gastric cancer cells (SGC-7901).

OBJECTIVE: To analyze the clinical features of overweight and obese rheumatoid arthritis (RA)patients, and the relationship between body mass index (BMI) and disease characteristics. METHODS: The demographic data, extra-articular manifestations, comorbidities, and disease activity of RA patients admitted to the Rheumatology and Immunology Department of Peking University Third Hospital from January 2015 to December 2020 were collected, and the above characteristics of overweight and obese RA patients were retrospectively analyzed. According to the WHO, BMI≥30 kg/m² referred to obese individuals, 25≤BMI < 30 kg/m² referred to overweight individuals, 18.5≤BMI < 25 kg/m² referred to normal individuals, BMI < 18.5 kg/m² referred to reduced body mass individuals. t test was used for the quantitative data in accordance with normal distribution. Wilcoxon rank sum test was used for the quantitative data of non-normal distribution. The qualitative data were analyzed by chi square test. But while 1≤theoretical frequency < 5, Chi square test of corrected four grid table was used. And Fisher exact probability method was used when theoretical frequency < 1. Analyzing whether overweight or obesity was associated with comorbidities using Logistic regression adjusted confounding factors. RESULTS: A total of 481 RA patients were included in this study, with an average BMI value of (23.28±3.75) kg/m².Of the patients, 31 cases (6.5%) were with BMI < 18.5 kg/m², 309 cases (64.2%) with 18.5≤ BMI < 25 kg/m², amounting to 340 cases (70.7%). There were 119 overweight individuals (25≤ BMI < 30 kg/m², 24.7%) and 22 obese individuals (BMI≥30 kg/m², 4.6%), totaling 141 (29.3%).The proportion of the overweight and obese RA patients suffering from hypertension (57.4% vs. 39.1%, P < 0.001), diabetes (25.5% vs. 15.0%, P=0.006), hyperlipidemia (22.7% vs. 10.9%, P=0.001), fatty liver (28.4% vs. 7.4%, P < 0.001), osteoarthritis (39.0% vs. 29.4%, P=0.040) was significantly higher, and the proportion of the patients with osteoporosis(59.6% vs. 70.9%, P=0.016) and anemia (36.2% vs. 55.6%, P < 0.001) was significantly lower. However, there was no difference between the two groups in coronary heart disease (5.7% vs. 7.6%, P=0.442), cerebrovascular disease (6.4% vs. 8.8%, P=0.372) and peripheral atherosclerosis (9.2% vs. 7.6%, P=0.565).The median C-reactive protein (CRP, 1.52 mg/dL vs. 2.35 mg/dL, P=0.008), median erythrocyte sedimentation rate (ESR, 34.0 mm/h vs. 50.0 mm/h, P=0.003), pain visual simulation score (VAS) (3.66±3.08 vs. 4.40±2.85, P=0.011), and 28 joint disease activity scores (DAS-28, 5.05±1.60 vs. 5.45±1.52, P=0.010) in the overweight and obese RA group were all lower than those in the normal and reduced weight groups. Multivariate regression analysis showed that overweight and obesity was an independent risk factor for hypertension, diabetes, hyperlipidemia and fatty liver, and had protective effects on osteoporosis and anemia. CONCLUSION In RA patients, RA disease activity is lower in overweight and obesity patients. Overweight and obesity is associated with hypertension, diabetes and hyperlipidemia, but not with cardiovascular and cerebrovascular diseases.
Humans ; Body Mass Index ; Overweight/epidemiology* ; Retrospective Studies ; Arthritis, Rheumatoid/epidemiology* ; Obesity/epidemiology* ; Diabetes Mellitus ; Hypertension/complications* ; Fatty Liver/complications* ; Hyperlipidemias/complications* ; Osteoporosis/complications* ; Anemia