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1.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 38(8): 935-941, 2024 Aug 15.
Article in Chinese | MEDLINE | ID: mdl-39175314

ABSTRACT

Objective: To investigate the feasibility and effectiveness of robot-assisted posterior minimally invasive access in treatment of thoracolumbar tuberculosis via transforaminal expansion approach. Methods: A clinical data of 40 patients with thoracolumbar tuberculosis admitted between January 2017 and May 2022 and met the selection criteria was retrospectively analyzed. Among them, 15 cases were treated with robot-assisted and minimally invasive access via transforaminal expansion approach for lesion removal, bone graft, and internal fixation (robotic group), and 25 cases were treated with traditional transforaminal posterior approach for lesion removal and intervertebral bone grafting (traditional group). There was no significant difference in the baseline data between the two groups ( P>0.05) in terms of gender, age, lesion segment, and preoperative American Spinal Injury Association (ASIA) grading, Cobb angle, visual analogue scale (VAS) score, erythrocyte sedimentation rate (ESR), and C reactive protein (CRP). The outcome indicators were recorded and compared between the two groups, including operation time, intraoperative bleeding volume, hospital stay, postoperative bedtime, complications, ESR and CRP before operation and at 1 week after operation, the level of serum albumin at 3 days after operation, VAS score and ASIA grading of neurological function before operation and at 6 months after operation, the implant fusion, fusion time, Cobb angle of the lesion, and the loss of Cobb angle observed by X-ray films and CT. The differences of ESR, CRP, and VAS score (change values) between pre- and post-operation were calculated and compared. Results: Compared with the traditional group, the operation time and intraoperative bleeding volume in the robotic group were significantly lower and the serum albumin level at 3 days after operation was significantly higher ( P<0.05); the postoperative bedtime and the length of hospital stay were also shorter, but the difference was not significant ( P>0.05). There were 2 cases of poor incision healing in the traditional group, but no complication occurred in the robotic group, and the difference in the incidence of complication between the two groups was not significant ( P>0.05). There were significant differences in the change values of ESR and CRP between the two groups ( P<0.05). All Patients were followed up, and the follow-up time was 12-18 months (mean, 13.0 months) in the traditional group and 12-16 months (mean, 13.0 months) in the robotic group. Imaging review showed that all bone grafts fused, and the difference in fusion time between the two groups was not significant ( P>0.05). The difference in Cobb angle between the pre- and post-operation in the two groups was significant ( P<0.05); and the Cobb angle loss was significant more in the traditional group than in the robotic group ( P<0.05). The VAS scores of the two groups significantly decreased at 6 months after operation when compared with those before operation ( P<0.05); the difference in the change values of VAS scores between the two groups was not significant ( P>0.05). There was no occurrence or aggravation of spinal cord neurological impairment in the two groups after operation. There was a significant difference in ASIA grading between the two groups at 6 months after operation compared to that before operation ( P<0.05), while there was no significant difference between the two groups ( P>0.05). Conclusion: Compared with traditional posterior open operation, the use of robot-assisted minimally invasive access via transforaminal approach for lesion removal and bone grafting internal fixation in the treatment of thoracolumbar tuberculosis can reduce the operation time and intraoperative bleeding, minimizes surgical trauma, and obtain definite effectiveness.


Subject(s)
Bone Transplantation , Lumbar Vertebrae , Minimally Invasive Surgical Procedures , Robotic Surgical Procedures , Thoracic Vertebrae , Tuberculosis, Spinal , Humans , Thoracic Vertebrae/surgery , Tuberculosis, Spinal/surgery , Lumbar Vertebrae/surgery , Robotic Surgical Procedures/methods , Minimally Invasive Surgical Procedures/methods , Treatment Outcome , Bone Transplantation/methods , Female , Male , Spinal Fusion/methods , Operative Time , Retrospective Studies , Postoperative Complications
2.
Int J Chron Obstruct Pulmon Dis ; 19: 1865-1878, 2024.
Article in English | MEDLINE | ID: mdl-39185395

ABSTRACT

Background: In human health, vitamins play a vital role in various metabolic and regulatory processes and in the proper functioning of cells. Currently, the effect of Vitamin E (VE) intake on multiple causes of death in Chronic obstructive pulmonary disease (COPD) patients is unclear. Therefore, this paper aims to investigate the relationship between VE and multiple causes of death in COPD patients, to guide the rationalization of dietary structure and reduce the risk of COPD death. Methods: This study screened patients with COPD aged ≥40 years from the National Health and Nutrition Examination Survey (NHANES) database 2008-2018. Weighted COX regression was used to analyze the association between VE intake and multiple causes of death in COPD. The restricted cubic spline(RCS) is drawn to show their relationship. Finally, we conducted a subgroup analysis for further verification. Results: A total of 1261 participants were included in this study. After adjustment for multiple covariates, VE intake was associated with all-cause death in COPD patients, and chronic lower respiratory disease (CLRD) deaths were linearly associated with cardiovascular disease (CVD) deaths there was no such correlation. Subgroup analyses showed no interaction between subgroups, further validating the robustness of the relationship. Conclusion: In COPD patients, VE intake was negatively associated with all-cause mortality and CLRD death. Higher VE intake reduces the risk of all-cause mortality and CLRD death in COPD patients.


Subject(s)
Cause of Death , Nutrition Surveys , Pulmonary Disease, Chronic Obstructive , Vitamin E , Humans , Pulmonary Disease, Chronic Obstructive/mortality , Pulmonary Disease, Chronic Obstructive/diagnosis , Male , Female , Vitamin E/administration & dosage , Middle Aged , Aged , United States/epidemiology , Risk Factors , Risk Assessment , Protective Factors , Time Factors , Adult
3.
Microbiol Spectr ; : e0021624, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39162522

ABSTRACT

Respiratory tract infections are the most common triggers for heart failure in elderly people. The healthy respiratory commensal microbiota can prevent invasion by infectious pathogens and decrease the risk of respiratory tract infections. However, upper respiratory tract (URT) microbiome in the elderly is not well understood. To comprehend the profiles of URT microbiota in the elderly, and the link between the microbiome and heart failure, we investigated the oropharyngeal (OP) microbiome of these populations in Heilongjiang Province, located in the North-East of China, a high-latitude and cold area with a high prevalence of respiratory tract infection and heart failure. Taxonomy-based analysis showed that six dominant phyla were represented in the OP microbial profiles. Compared with young adults, the OP in the elderly exhibited a significantly different microbial community, mainly characterized by highly prevalent Streptococcus, unidentified_Saccharibacteria, Veillonella, unidentified_Pre votellaceae, and Neisseria. While unidentified_Prevotellaceae dominated in the young OP microbiome. There was competition for niche dominance between Streptococcus and member of Prevotellaceae in the OP. Correlation analysis revealed that the abundance of unidentified_Saccharibacteria was positive, while Streptococcus was negatively correlated to age among healthy elderly. The bacterial structure and abundance in the elderly with heart failure were much like healthy controls. Certain changes in microbial diversity indicated the potential OP microbial disorder in heart failure patients. These results presented here identify the respiratory tract core microbiota in high latitude and cold regions, and reveal the robustness of OP microbiome in the aged, supplying the basis for microbiome-targeted interventions.IMPORTANCETo date, we still lack available data on the oropharyngeal (OP) microbial communities in healthy populations, especially the elderly, in high latitude and cold regions. A better understanding of the significantly changed respiratory tract microbiota in aging can provide greater insight into characteristics of longevity and age-related diseases. In addition, determining the relationship between heart failure and OP microbiome may provide novel prevention and therapeutic strategies. Here, we compared OP microbiome in different age groups and elderly people with or without heart failure in northeastern China. We found that OP microbial communities are strongly linked to healthy aging. And the disease status of heart failure was not a powerful factor affecting OP microbiome. The findings may provide basic data to reveal respiratory bacterial signatures of individuals in a cold geographic region.

4.
Invest Ophthalmol Vis Sci ; 65(10): 4, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39087932

ABSTRACT

Purpose: Local recurrence predicts dismal prognosis in eyelid sebaceous carcinoma (SC). Recurrence predictors vary across studies. Accurate recurrence estimation is essential for individualized therapy in eyelid SC. This study aims to identify recurrence predictors and develop a nomogram for personalized prediction in eyelid SC. Methods: We conducted a multicenter retrospective cohort study. Chart reviews were performed in 418 consecutive patients with eyelid SC. All patients were followed up after their initial surgery. Multivariate Cox regression was used to explore the independent predictors of recurrence. A nomogram for recurrence prediction was developed and validated with bootstrap resampling. The predictive accuracy and discriminative ability were compared with the Tumor, Node, Metastasis (TNM) staging system. Results: Over a median of 60-month follow-up, 167 patients (40%) had local recurrence. The median time from diagnosis to recurrence was 14 months. The 1-year cumulative recurrence rate was 18%. Diagnostic delay (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 1.00-1.01, P = 0.001), orbital involvement (HR = 4.47, 95% CI = 3.04-6.58, P < 0.001), Ki67 (HR = 1.01, 95% CI = 1.00-1.02, P = 0.008) and initial surgery of Mohs micrographic surgery with intraoperative frozen section control (HR = 0.53, 95% CI = 0.35-0.80, P = 0.003) were independent influencing factors of recurrence. A nomogram integrating these four factors combined with pagetoid spread displayed satisfactory discriminative ability (C-index = 0.80-0.83; area under the curve [AUC] = 0.82-0.84), which compared favorably than TNM staging (all P < 0.05). Conclusions: The recurrence rate is high in eyelid SC. Early detection and primary resection with Mohs micrographic surgery are recommended in controlling recurrence. Patients with orbital involvement, high Ki67 expression, and pagetoid spread may require adjuvant measures. This nomogram offers more accurate recurrence estimates, aiding in therapeutic decision making.


Subject(s)
Adenocarcinoma, Sebaceous , Eyelid Neoplasms , Neoplasm Recurrence, Local , Nomograms , Sebaceous Gland Neoplasms , Humans , Male , Female , Retrospective Studies , Eyelid Neoplasms/pathology , Eyelid Neoplasms/diagnosis , Sebaceous Gland Neoplasms/pathology , Sebaceous Gland Neoplasms/diagnosis , Middle Aged , Aged , Adenocarcinoma, Sebaceous/pathology , Adenocarcinoma, Sebaceous/diagnosis , Follow-Up Studies , Neoplasm Staging , Aged, 80 and over , Adult , Prognosis
5.
Int J Nurs Stud ; 159: 104871, 2024 Aug 06.
Article in English | MEDLINE | ID: mdl-39197307

ABSTRACT

BACKGROUND: With the dramatic rise in the number of older cancer patients, the question of whether or not to tell older patients of bad news becomes an urgent and common challenge. However, existing studies concentrated on the three types of disclosure decisions and their reasons, including full disclosure, partial disclosure, and avoidance of disclosure, and the evolution process and factors influencing family members' disclosure decisions are unclear. OBJECTIVE: Explore the experience and factors of the shift between disclosure and concealment among family members of older cancer patients. METHODS: A qualitative study was employed. Semi-structured interviews were conducted with 33 family members at two general hospitals and one community hospital between December 2022 and June 2023. The interview data were analyzed using a content analysis approach. RESULTS: The treatment plan symbolizes the "hope of survival" and it is the fundamental factor for the shift between concealment and disclosure. There are three themes of family members in making decisions during the diagnostic and therapeutic process: (a) When bad news is approaching: Keep calm in the midst of chaos, (b) when a treatment plan is determined: Hope for survival dictates disclosure decisions, and (c) when the patient's disease deteriorated: Finding hope in hopelessness. CONCLUSIONS: Disclosure and concealment are a complex and dynamic process. The factor of the shift lies in the "hope of survival" symbolized by the treatment plan. The key to disclosure by family members is to give patients enough hope to control or cure a patient's disease, or prolong the life of patients and improve their quality of life.

6.
Front Immunol ; 15: 1452078, 2024.
Article in English | MEDLINE | ID: mdl-39144141

ABSTRACT

Lung cancer (LC) is one of the most common cancer worldwide. Tumor-associated macrophages (TAMs) are important component of the tumor microenvironment (TME) and are closely related to the stages of tumor occurrence, development, and metastasis. Macrophages are plastic and can differentiate into different phenotypes and functions under the influence of different signaling pathways in TME. The classically activated (M1-like) and alternatively activated (M2-like) represent the two polarization states of macrophages. M1 macrophages exhibit anti-tumor functions, while M2 macrophages are considered to support tumor cell survival and metastasis. Macrophage polarization involves complex signaling pathways, and blocking or regulating these signaling pathways to enhance macrophages' anti-tumor effects has become a research hotspot in recent years. At the same time, there have been new discoveries regarding the modulation of TAMs towards an anti-tumor phenotype by synthetic and natural drug components. Nanotechnology can better achieve combination therapy and targeted delivery of drugs, maximizing the efficacy of the drugs while minimizing side effects. Up to now, nanomedicines targeting the delivery of various active substances for reprogramming TAMs have made significant progress. In this review, we primarily provided a comprehensive overview of the signaling crosstalk between TAMs and various cells in the LC microenvironment. Additionally, the latest advancements in novel drugs and nano-based drug delivery systems (NDDSs) that target macrophages were also reviewed. Finally, we discussed the prospects of macrophages as therapeutic targets and the barriers to clinical translation.


Subject(s)
Lung Neoplasms , Signal Transduction , Tumor Microenvironment , Tumor-Associated Macrophages , Tumor Microenvironment/immunology , Humans , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Animals , Macrophage Activation/immunology
7.
Food Chem ; 460(Pt 3): 140741, 2024 Dec 01.
Article in English | MEDLINE | ID: mdl-39128372

ABSTRACT

Xanthine oxidase (XO) inhibitory peptides can prevent XO-mediated hyperuricemia. Currently, QSAR about XO inhibitory peptides with different lengths remains to be enriched. Here, XO inhibitory peptides were obtained from porcine visceral proteins through virtual-screening. A prediction model was established by machine-learning. Virtual-screening retained four lengths of peptides, including 3-6. Molecular-docking recognized their binding sites with XO and showed residues W, F, and G were the key amino acids. Datasets of XO inhibitory peptides therewith were established. The optimal model was used to generalize the peptides reported. Results showed that the R2 of the tripeptide, tetrapeptide, pentapeptide and hexapeptide in the generalisation test were R2 = 0.81, R2 = 0.82, R2 = 0.83 and R2 = 0.83, respectively. Overall, this work can serve as a reference for explaining the activity mechanism of XO inhibitory peptides and predicting the activity of XO inhibitory peptides.


Subject(s)
Enzyme Inhibitors , Machine Learning , Peptides , Xanthine Oxidase , Xanthine Oxidase/chemistry , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/metabolism , Animals , Peptides/chemistry , Peptides/pharmacology , Swine , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Binding Sites
8.
MedComm (2020) ; 5(9): e695, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39161800

ABSTRACT

Cellular senescence, one of the hallmarks of cancer, is characterized by cell cycle arrest and the loss of most normal cellular functions while acquiring a hypersecretory, proinflammatory phenotype. The function of senescent cells in cancer cells varies depending on the cellular conditions. Before the occurrence of cancer, senescent cells act as a barrier to prevent its development. But once cancer has occurred, senescent cells play a procancer role. However, few of the current studies have adequately explained the diversity of cellular senescence across cancers. Herein, we concluded the latest intrinsic mechanisms of cellular senescence in detail and emphasized the senescence-associated secretory phenotype as a key contributor to heterogeneity of senescent cells in tumor. We also discussed five kinds of inducers of cellular senescence and the advancement of senolytics in cancer, which are drugs that tend to clear senescent cells. Finally, we summarized the various effects of senescent cells in different cancers and manifested that their functions may be diametrically opposed under different circumstances. In short, this paper contributes to the understanding of the diversity of cellular senescence in cancers and provides novel insight for tumor therapy.

9.
PLoS Genet ; 20(7): e1011339, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38980841

ABSTRACT

BACKGROUND: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. METHODS: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. FINDINGS: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10-31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. CONCLUSIONS: Our findings highlight the importance of causal genes for VV and provide new directions for treatment.


Subject(s)
Exome Sequencing , Exome , Genetic Predisposition to Disease , Genome-Wide Association Study , Varicose Veins , Humans , Varicose Veins/genetics , Female , Male , Exome/genetics , Polymorphism, Single Nucleotide , Endothelin-Converting Enzymes/genetics , Middle Aged , Genetic Variation , Adult , Ion Channels
10.
Nat Hum Behav ; 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38987357

ABSTRACT

Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer's disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG, PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

11.
Alzheimers Dement ; 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39023044

ABSTRACT

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

12.
Mol Divers ; 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38970641

ABSTRACT

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a crucial serine/threonine protein kinase that belongs to the IRAK family and plays a pivotal role in Toll-like receptor (TLR) and Interleukin-1 receptor (IL-1R) signaling pathways. Due to IRAK4's significant role in immunity, inflammation, and malignancies, it has become an intriguing target for discovering and developing potent small-molecule inhibitors. Consequently, there is a pressing need for rapid and accurate prediction of IRAK4 inhibitor activity. Leveraging a comprehensive dataset encompassing activity data for 1628 IRAK4 inhibitors, we constructed a prediction model using the LightGBM algorithm and molecular fingerprints. This model achieved an R2 of 0.829, an MAE of 0.317, and an RMSE of 0.460 in independent testing. To further validate the model's generalization ability, we tested it on 90 IRAK4 inhibitors collected in 2023. Subsequently, we applied the model to predict the activity of 13,268 compounds with docking scores less than - 9.503 kcal/mol. These compounds were initially screened from a pool of 1.6 million molecules in the chemdiv database through high-throughput molecular docking. Among these, 259 compounds with predicted pIC50 values greater than or equal to 8.00 were identified. We then performed ADMET predictions on these selected compounds. Finally, through a rigorous screening process, we identified 34 compounds that adhere to the four complementary drug-likeness rules, making them promising candidates for further investigation. Additionally, molecular dynamics simulations confirmed the stable binding of the screened compounds to the IRAK4 protein. Overall, this work presents a machine learning model for accurate prediction of IRAK4 inhibitor activity and offers new insights for subsequent structure-guided design of novel IRAK4 inhibitors.

13.
Nat Commun ; 15(1): 5924, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39009607

ABSTRACT

The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves' disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.


Subject(s)
Exome Sequencing , Filaggrin Proteins , Humans , Male , Female , Adult , Genetic Predisposition to Disease/genetics , Middle Aged , Immune System Diseases/genetics , Mendelian Randomization Analysis , Mutation , Proteomics , Genetic Variation , Asthma/genetics , Asthma/immunology , Aged , Dermatitis, Atopic/genetics , Dermatitis, Atopic/immunology
14.
J Affect Disord ; 362: 323-333, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-38971194

ABSTRACT

BACKGROUND: Shift work is associated with susceptibility to several neuropsychiatric disorders. This study aims to investigate the effect of shift work on the incidence of neuropsychiatric disorders, and highlighting how individual variability may influence the association. METHODS: UK Biobank participants with employment information were included. Cox survival was conducted in main and subgroup analyses. Correlation analyses explored the impact of shift work on brain structures, and mediation analyses were performed to elucidate the shared underlying mechanisms. Shift work tolerance was evaluated through survival analyses contrasting the risks associated with five neuropsychiatric disorders in shift versus non-shift workers across different demographic or occupational strata. RESULTS: The analysis encompassed 254,646 participants. Shift work was associated with higher risk of dementia (HR 1.29, 95 % CI 1.10-1.52), anxiety (1.08, 1.01-1.15), depression (1.29, 1.22-1.36), and sleep disorders (1.18, 1.09-1.28), but not stroke (p = 0.20). Shift work was correlated with decreasing volume of various brain regions, particularly in thalamus, lateral orbitofrontal, and middle temporal. Mediation analysis revealed that increased immune response and glucose levels are common pathways linking shift work to these disorders. We observed diversity in shift work tolerance across different individual characteristics, among which socioeconomic status and length of working hours were the most essential. LIMITATIONS: Self-reported employment information may cause misclassification and recall bias. And since we focused on the middle-aged population, the conclusions may not be representative of younger or older populations. CONCLUSIONS: Our findings indicated the need to monitor shift worker health and provide personalized management to help adapt to shift work.


Subject(s)
Shift Work Schedule , Humans , Male , Female , Middle Aged , Shift Work Schedule/adverse effects , United Kingdom/epidemiology , Adult , Incidence , Aged , Dementia/epidemiology , Work Schedule Tolerance/physiology , Anxiety/epidemiology , Sleep Wake Disorders/epidemiology , Brain/physiopathology , Mental Disorders/epidemiology , Depression/epidemiology
15.
J Transl Med ; 22(1): 605, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38951874

ABSTRACT

BACKGROUND: Uveal melanoma (UM), the most common adult intraocular tumor, is characterized by high malignancy and poor prognosis in advanced stages. Angiogenesis is critical for UM development, however, not only the role of vascular endothelial dysfunction in UM remains unknown, but also their analysis at the single-cell level has been lacking. A comprehensive analysis is essential to clarify the role of the endothelium in the development of UM. METHODS: By using single-cell RNA transcriptomics data of 11 cases of primary and liver metastasis UM, we analyzed the endothelial cell status. In addition, we analyzed and validated ECs in the in vitro model and collected clinical specimens. Subsequently, we explored the impact of endothelial dysfunction on UM cell migration and explored the mechanisms responsible for the endothelial cell abnormalities and the reasons for their peripheral effects. RESULTS: UM metastasis has a significantly higher percentage of vascular endothelial cells compared to in situ tumors, and endothelial cells in metastasis show significant senescence. Senescent endothelial cells in metastatic tumors showed significant Krüppel-like factor 4 (KLF4) upregulation, overexpression of KLF4 in normal endothelial cells induced senescence, and knockdown of KLF4 in senescent endothelium inhibited senescence, suggesting that KLF4 is a driver gene for endothelial senescence. KLF4-induced endothelial senescence drove tumor cell migration through a senescence-associated secretory phenotype (SASP), of which the most important component of the effector was CXCL12 (C-X-C motif chemokine ligand 12), and participated in the composition of the immunosuppressive microenvironment. CONCLUSION: This study provides an undesirable insight of senescent endothelial cells in promoting UM metastasis.


Subject(s)
Cell Movement , Cellular Senescence , Endothelial Cells , Kruppel-Like Factor 4 , Liver Neoplasms , Melanoma , Single-Cell Analysis , Uveal Neoplasms , Humans , Uveal Neoplasms/pathology , Uveal Neoplasms/genetics , Melanoma/pathology , Melanoma/genetics , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Liver Neoplasms/genetics , Endothelial Cells/metabolism , Endothelial Cells/pathology , Kruppel-Like Transcription Factors/metabolism , Kruppel-Like Transcription Factors/genetics , Cell Line, Tumor , Chemokine CXCL12/metabolism , Chemokine CXCL12/genetics , Gene Expression Regulation, Neoplastic , Female , Male
16.
Adv Sci (Weinh) ; : e2401748, 2024 Jul 12.
Article in English | MEDLINE | ID: mdl-38994891

ABSTRACT

Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment-resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2-activating transcription factor 4-alanine, serine, cysteine-preferring transporter 2 (GCN2-ATF4-ASCT2) axis. Central to this phenomenon is the stress-induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G-quadruplex structure located within the promoter region of ATF4 (ATF4-G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4-G4. For the first time, the high-resolution structure of the COP-ATF4-G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP-2 alpha (TFAP2A) and ATF4-G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4-G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine-restricted therapy.

17.
Int J Biol Macromol ; 274(Pt 2): 133172, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38880458

ABSTRACT

In the field of bone tissue repair, the treatment of bone defects has always posed a significant challenge. In recent years, the advancement of bone tissue engineering and regenerative medicine has sparked great interest in the development of innovative bone grafting materials. In this study, a novel hydroxyapatite (HA) material was successfully prepared and comprehensively characterized. Antimicrobial experiments and biological evaluations were conducted to determine its efficacy. Based on the aforementioned research findings, 3D printing technology was employed to fabricate HA/chitosan (CS)/ polycaprolactone (PCL) scaffolds. The composition of the scaffold materials was confirmed through X-ray diffractometer (XRD) and Fourier Transform Infrared Spectroscopy (FT-IR) tests, while the influence of different HA ratios on the scaffold surface morphology was observed. Additionally, antimicrobial experiments demonstrated the favorable antimicrobial activity of the scaffolds containing 30%HA + 5%CS + PCL. Furthermore, the water contact angle measurements confirmed the superhydrophilicity of the scaffolds. Finally, the excellent bioactivity and ability to promote tissue regeneration of the scaffolds were further confirmed by in vitro and in vivo experiments. This study provides new options for future repair and regeneration of bone tissue and clinical applications.


Subject(s)
Chitosan , Durapatite , Polyesters , Printing, Three-Dimensional , Tissue Engineering , Tissue Scaffolds , Chitosan/chemistry , Durapatite/chemistry , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Animals , Polyesters/chemistry , Bone and Bones/drug effects , Bone Regeneration/drug effects , Animal Scales/chemistry , Fishes , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Spectroscopy, Fourier Transform Infrared
18.
Geroscience ; 46(5): 5365-5385, 2024 Oct.
Article in English | MEDLINE | ID: mdl-38837026

ABSTRACT

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.


Subject(s)
Exome Sequencing , Repressor Proteins , Humans , Male , Repressor Proteins/genetics , Female , Dioxygenases/genetics , Proto-Oncogene Proteins/genetics , DNA-Binding Proteins/genetics , Aging/genetics , Middle Aged , Aged , Genome-Wide Association Study , Telomere Homeostasis/genetics , Leukocytes/metabolism , Telomere/genetics , Neoplasms/genetics , Exome/genetics
19.
J Affect Disord ; 358: 35-41, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38705529

ABSTRACT

BACKGROUND: Cancer patients have a higher risk of depression and are associated with severe adverse prognosis. The relationship between leisure-time physical activity (LTPA) and depressive symptoms in cancer patients is currently unclear. Therefore, our study mainly explores the potential association between LTPA and the weekly cumulative time of LTPA with depressive symptoms in cancer patients. METHODS: We included and analyzed 3368 cancer patients (aged >20 years) from the National Health and Nutrition Examination Survey (NHANES) of the United States from 1999 to 2018. The LTPA score was evaluated through a self-report questionnaire, while depressive symptoms were evaluated through the Health Questionnaire-9 (PHQ-9). Multiple logistic regression analysis was used to explore the relationship between LTPA duration and the occurrence of cancer-related depressiive symptoms. Linear correlation was studied using the restricted cubic spline method. RESULTS: According to a fully adjusted multivariate logistic regression model with confounding variables, the odds ratio (OR) between LTPA and depressive symptoms in cancer patients in this study was 0.59 (95 % confidence interval = 0.39, 0.92; P = 0.02). When the LTPA level was ≥300 min/week, the incidence of depressive symptoms was reduced by 59 % (OR = 0.41, 95 % CI = 0.21, 0.83). In addition, the cubic spline method was used to obtain a linear negative correlation between LTPA duration and tumor depressive symptoms. CONCLUSION: LTPA was negatively correlated with cancer-related depressive symptoms, and the cumulative time of LTPA/week was linearly correlated with depressive symptoms. The slope of the benefit curve changed significantly when the cumulative time of LTPA reached 600 min per week, suggesting that appropriately increasing LTPA had significant benefits on mental health of cancer patients.


Subject(s)
Depression , Exercise , Leisure Activities , Neoplasms , Nutrition Surveys , Humans , Male , Female , Neoplasms/psychology , Neoplasms/epidemiology , Depression/epidemiology , Depression/psychology , Middle Aged , Adult , United States/epidemiology , Aged , Cross-Sectional Studies , Logistic Models
20.
ACS Omega ; 9(17): 19440-19450, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38708237

ABSTRACT

Calcium silicate (CS), a new and important bioceramic bone graft material, is prepared by using eggshells, which have a porous structure and are rich in calcium ions. Furthermore, the preparation of new CS materials using eggshells and diatomaceous earth minimizes their negative impact on the environment. In this study, we prepared CS materials using a high-temperature calcination method. The composition of the material was demonstrated by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analysis. Scanning electron microscopy (SEM) analysis confirmed the porous structure of the CS material. We also introduced ZnO to prepare ZnO-CS with antibacterial properties and showed that ZnO-CS exhibits excellent antibacterial effects through in vitro antibacterial experiments. Subsequent in vitro mineralization experiments demonstrated that ZnO-CS promoted the formation of a hydroxyapatite layer. Furthermore, in vitro cytotoxicity experiments demonstrated that ZnO-CS had very good biosafety and promoted cell proliferation. These findings were confirmed through subsequent cell proliferation experiments. Our results indicate that the novel ZnO-CS is a promising candidate for bone tissue engineering.

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