Gefitinib,a first-generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibi-tor(TKI),exerts significant therapeutic efficacy in the treatment of non-small cell lung cancer(NSCLC)by selectively targeting mutant forms of EGFR.However,the development of acquired resistance signifi-cantly limits its long-term clinical benefits.Cell division cycle 20(CDC20),a key regulator of cell cycle progression,has been implicated in the tumorigenesis and progression of various malignancies.Neverthe-less,its role and underlying regulatory mechanisms in the acquisition of drug resistance in NSCLC remain largely unexplored.This study aimed to elucidate the molecular mechanisms by which CDC20 contributes to gefitinib resistance in NSCLC.Gefitinib-resistant cell lines,HCC827/GR(ICs0 0.05±0.01 μmnol/L vs 36.24±6.21 μmol/L)and PC9/GR(IC50 0.02±0.01 μmol/L vs 25.36±5.57 μmol/L),were established through stepwise drug induction,exhibiting markedly increased IC50 values compared to their parental counterparts.Bioinformatics analysis revealed that the transcriptional level of CDC20 is signifi-cantly upregulated in lung cancer tissues and is associated with poor patient prognosis.Western blotting analysis confirmed elevated CDC20 protein levels in the resistant HCC827/GR and PC9/GR cells relative to the parental HCC827 and PC9 cells.To further investigate the functional role of CDC20 in NSCLC ge-fitinib resistance,CDC20 was knocked out using CRISPR/Cas9 technology.This genetic intervention sig-nificantly restored gefitinib sensitivity in resistant cells(IC 50 37.08±6.15 μmol/L vs 10.49±1.83μmol/L,7.23±1.55 μamol/L),while concurrently promoting apoptosis and inducing G2/M phase cell cycle arrest.Conversely,CDC20 overexpression decreased drug sensitivity in parental cells and notably attenuated gefitinib-induced apoptosis and cell cycle arrest.Mechanistically,CDC20 depletion was found to inhibit activation of the PI3K/Akt/mTOR signaling pathway,upregulate pro-apoptotic proteins such as cleaved-Caspase 3 and Bax,and downregulate the anti-apoptotic protein Bcl-2.Collectively,these find-ings demonstrate that CDC20 mediates gefitinib resistance in NSCLC through modulation of the PI3K/Akt/mTOR signaling pathway,thereby identifying CDC20 as a potential therapeutic target for overcoming resistance to EGFR-targeted therapies.

Objective:To explore the dosimetry optimization strategy based on filter thickness and shape selection for the bulb superficial X-ray radiotherapy unit.Methods:Monte Carlo code TOPAS was used to model tubular equipment, and the dose distribution from six X-ray energies (50-150 kV) and five conventional aluminum filters (0.5-3.0 mm) with different thickness were simulated in the water model. The percentage depth dose (PDD) curve along the central axis, the center-axis profile dose at different depths, and the lateral dose distribution were analyzed. The dose distribution of three different designs of aluminum filters (conventional cylindrical, conical and oblique cylindrical filters) was compared to evaluate the effect of dosimetric optimization of different filter shapes.Results:Under the same energy, increasing the thickness of the filter can optimize the superficial skin dose, and the optimization effect of depth dose uniformity can be increased by 26% at a depth of 5.5 mm at 70 kV energy. The raised, flat and inclined dose distribution modes can be achieved by using conventional cylindrical, conical and inclined aluminum filters.Conclusions:By selecting the appropriate X-ray energy and filter thickness, an ideal dose distribution matching the tumor depth can be achieved. The application of personalized filters is also of great significance for diverse target areas.

Gefitinib,a first-generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibi-tor(TKI),exerts significant therapeutic efficacy in the treatment of non-small cell lung cancer(NSCLC)by selectively targeting mutant forms of EGFR.However,the development of acquired resistance signifi-cantly limits its long-term clinical benefits.Cell division cycle 20(CDC20),a key regulator of cell cycle progression,has been implicated in the tumorigenesis and progression of various malignancies.Neverthe-less,its role and underlying regulatory mechanisms in the acquisition of drug resistance in NSCLC remain largely unexplored.This study aimed to elucidate the molecular mechanisms by which CDC20 contributes to gefitinib resistance in NSCLC.Gefitinib-resistant cell lines,HCC827/GR(ICs0 0.05±0.01 μmnol/L vs 36.24±6.21 μmol/L)and PC9/GR(IC50 0.02±0.01 μmol/L vs 25.36±5.57 μmol/L),were established through stepwise drug induction,exhibiting markedly increased IC50 values compared to their parental counterparts.Bioinformatics analysis revealed that the transcriptional level of CDC20 is signifi-cantly upregulated in lung cancer tissues and is associated with poor patient prognosis.Western blotting analysis confirmed elevated CDC20 protein levels in the resistant HCC827/GR and PC9/GR cells relative to the parental HCC827 and PC9 cells.To further investigate the functional role of CDC20 in NSCLC ge-fitinib resistance,CDC20 was knocked out using CRISPR/Cas9 technology.This genetic intervention sig-nificantly restored gefitinib sensitivity in resistant cells(IC 50 37.08±6.15 μmol/L vs 10.49±1.83μmol/L,7.23±1.55 μamol/L),while concurrently promoting apoptosis and inducing G2/M phase cell cycle arrest.Conversely,CDC20 overexpression decreased drug sensitivity in parental cells and notably attenuated gefitinib-induced apoptosis and cell cycle arrest.Mechanistically,CDC20 depletion was found to inhibit activation of the PI3K/Akt/mTOR signaling pathway,upregulate pro-apoptotic proteins such as cleaved-Caspase 3 and Bax,and downregulate the anti-apoptotic protein Bcl-2.Collectively,these find-ings demonstrate that CDC20 mediates gefitinib resistance in NSCLC through modulation of the PI3K/Akt/mTOR signaling pathway,thereby identifying CDC20 as a potential therapeutic target for overcoming resistance to EGFR-targeted therapies.

Metabolic-associated fatty liver disease (MAFLD) and osteoporosis (OP) are two very common metabolic diseases. A growing body of experimental evidence supports a pathophysiological link between MAFLD and OP. MAFLD is often associated with the development of OP. Rutaecarpine (RUT) is one of the main active components of Chinese medicine Euodiae Fructus. Our previous studies have demonstrated that RUT has lipid-lowering, anti-inflammatory and anti-atherosclerotic effects, and can improve the OP of rats. However, whether RUT can improve both fatty liver and OP symptoms of MAFLD mice at the same time remains to be investigated. In this study, we used C57BL/6 mice fed a high-fat diet (HFD) for 4 months to construct a MAFLD model, and gave the mice a low dose (5 mg·kg^-1) and a high dose (15 mg·kg^-1) of RUT by gavage for 4 weeks. The effects of RUT on liver steatosis and bone metabolism were then evaluated at the end of the experiment [this experiment was approved by the Experimental Animal Ethics Committee of Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences (approval number: IMB-20190124D₃03)]. The results showed that RUT treatment significantly reduced hepatic steatosis and lipid accumulation, and significantly reduced bone loss and promoted bone formation. In summary, this study shows that RUT has an effect of improving fatty liver and OP in MAFLD mice.

Ergonomic Principle for the Prevention of Work-Related Musculoskeletal Disorders Part 1: General Principles (T/WSJD 14.1-2020) is the first guideline standard for the prevention of work-related musculoskeletal disorders provided to employers and occupational health technical service institutions in China, which covers ergonomic risk factors and their hazard definition, ergonomic prevention principles, risk assessment process, risk control process and risk evaluation principles. The standard specifically clarify the specific types of adverse ergonomic risk factors and control strategies and the standard process of systematic ergonomic risk assessment, providing implementation paths and practical guidance for eliminating/reducing adverse ergonomic risks and enhance workplace environments to prevent work-related musculoskeletal disorders. This paper interprets and analyzes the background of standard establishment, formulation process, fundamental basis, and main content, etc., to provide scientific and accurate technical support for enterprise managers, labours and technical personnel of occupational health institutions to optimize the use of this standard.

The "Guidelines for the Ergonomic Prevention of Work-related Musculoskeletal Disorders Part 3 in Shipbuilding Operations" (T/WSJD 14.3-2024) was published and implemented in March 2024, providing a basis for scientific prevention and control of musculoskeletal disorders in shipbuilding operations. In this paper, the background, formulation process, basis and main content of the standard project are interpreted and analyzed, so as to help relevant practitioners and managers more fully understand and implement the ergonomic program proposed by the standard, and provide scientific and accurate technical support for enterprises.

Objective:To explore the structural relationship between WMSDs in the upper limbs and various risk factors in the occupational population in China, based on a large sample epidemiological survey and structural equation analysis, and to establish a structural equation model, so as to lay a foundation for the prevention and control of such diseases.Methods:The Chinese version of the Musculoskeletal Disorders Electronic Questionnaire was used to conduct a nationwide survey on the prevalence of WMSDs in the upper extremity. Six factors related to WMSDs in the upper extremity were extracted by the classification standard of adverse ergonomic factors and their source and confirmatory factor analysis, including work organization, work type, upper extremity work posture, individual factors, upper extremity fatigue and upper extremity WMSDs. The structural equation analysis was carried out and the structural equation model was established.Results:The incidence of WMSDs and fatigue in the upper limbs was 24.44% and 43.76%, respectively. The adjusted structural equation model fitting indicators were generally up to the standard (GFI=1.000, AGFI=1.000, RMSEA=0.043, NFI=0.808, TLI=0.784) . The four exogenous latent variables of work organization, work type, upper limb work posture and individual factors were correlated. There was a strong positive correlation between job type and upper limb work posture ( r=0.865) , a moderate positive correlation between work organization and job type and upper limb work posture ( r=0.570, 0.490) , and a weak negative correlation between individual factors and the other three exogenous latent variables. Upper limb work posture and individual factors had direct effects on upper limb WMSDs, and the effect coefficients were 0.10 and 0.06, respectively. Upper limb fatigue played a mediating role between work organization, work type, upper limb work posture and upper limb WMSDs. The effect coefficient was 0.46, and the composition ratios of indirect effects were 100.0%, 100.0%, and 38.3%, respectively. The direct path effect of upper limb work posture, individual factors and upper limb WMSDs was weaker than the mediating path through upper limb fatigue. Conclusion:When carrying out the prevention and control of upper limbWMSDs, it is necessary to comprehensively consider the pathogenesis path of upper limb muscle fatigue and upper limb WMSDs caused by work organization, work type, and upper limb work posture, so as to provide theoretical reference for improving the prevention and control level of such diseases.

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: This study aimed to explore the interplay between the life-course body mass index (BMI) trajectories and insulin resistance (IR) on incident diabetes. METHODS: This longitudinal cohort included 2,336 participants who had BMI repeatedly measured 3-8 times between 1989 and 2009, as well as glucose and insulin measured in 2009. BMI trajectories were identified using a latent class growth mixed model. The interplay between BMI trajectories and IR on diabetes was explored using the four-way effect decomposition method. Logistic regression and mediation models were used to estimate the interaction and mediation effects, respectively. RESULTS: Three distinct BMI trajectory groups were identified: low-stable ( n = 1,625), medium-increasing ( n = 613), and high-increasing ( n = 98). Both interaction and mediation effects of BMI trajectories and IR on incident diabetes were significant ( P < 0.05). The proportion of incident diabetes was higher in the IR-obesity than in the insulin-sensitivity (IS) obesity group (18.9% vs. 5.8%, P < 0.001). After adjusting for covariates, the odds ratios (95% confidence intervals) of the IR, IS-obesity, and IR-obesity groups vs. the normal group were 3.22 (2.05, 5.16), 2.05 (1.00, 3.97), and 7.98 (5.19, 12.62), respectively. IR mediated 10.7% of the total effect of BMI trajectories on incident diabetes ( P < 0.001). CONCLUSION We found strong interactions and weak mediation effects of IR on the relationship between life-course BMI trajectories and incident diabetes. IS-obesity is associated with a lower risk of incident diabetes than IR-obesity.
Humans ; Insulin Resistance ; Body Mass Index ; Male ; Female ; Middle Aged ; China/epidemiology* ; Adult ; Longitudinal Studies ; Incidence ; Diabetes Mellitus/epidemiology* ; Aged ; Obesity/epidemiology* ; Diabetes Mellitus, Type 2/epidemiology* ; East Asian People