BACKGROUND: In the interim analysis of MONARCH plus, adding abemaciclib to endocrine therapy (ET) improved progression-free survival (PFS) and objective response rate (ORR) in predominantly Chinese postmenopausal women with HR+/HER2- advanced breast cancer (ABC). This study presents the final pre-planned PFS analysis. METHODS: In the phase III MONARCH plus study, postmenopausal women in China, India, Brazil, and South Africa with HR+/HER2- ABC without prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) were randomized (2:1) to abemaciclib (150 mg twice daily [BID]) or placebo plus: anastrozole (1.0 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg on days 1 and 15 of cycle 1 and then on day 1 of each subsequent cycle) (cohort B). The primary endpoint was PFS of cohort A. Secondary endpoints included cohort B PFS (key secondary endpoint), ORR, overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: In cohort A (abemaciclib: n  = 207; placebo: n  = 99), abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs . placebo (28.27 months vs . 14.73 months, hazard ratio [HR]: 0.476; 95% confidence interval [95% CI]: 0.348-0.649). In cohort B (abemaciclib: n  = 104; placebo: n  = 53), abemaciclib plus fulvestrant improved median PFS vs . placebo (11.41 months vs . 5.59 months, HR: 0.480; 95% CI: 0.322-0.715). Abemaciclib numerically improved ORR. Although immature, a trend toward OS benefit with abemaciclib was observed (cohort A: HR: 0.893, 95% CI: 0.553-1.443; cohort B: HR: 0.512, 95% CI: 0.281-0.931). The most frequent grade ≥3 adverse events in the abemaciclib arms were neutropenia, leukopenia, anemia (both cohorts), and lymphocytopenia (cohort B). Abemaciclib did not cause clinically meaningful changes in patient-reported global health, functioning, or most symptoms vs . placebo. CONCLUSIONS: Abemaciclib plus ET led to improvements in PFS and ORR, a manageable safety profile, and sustained HRQoL, providing clinical benefit without a high toxicity burden or reduced quality of life. TRIAL REGISTRATION ClinicalTrials.gov (NCT02763566).
Humans ; Female ; Fulvestrant/therapeutic use* ; Breast Neoplasms/metabolism* ; Aminopyridines/therapeutic use* ; Benzimidazoles/therapeutic use* ; Middle Aged ; Aromatase Inhibitors/therapeutic use* ; Aged ; Receptor, ErbB-2/metabolism* ; Adult ; Letrozole/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Anastrozole/therapeutic use*

Objectives miR-207 has been identified as being expressed in natural killer (NK) cell exosomes that play a role in disease progression; however, to date, there are no studies specifically linking miR-207 to tuberculosis (TB). Methods Bioinformatics methods employed for prediction, followed by a dual luciferase reporter assay to determine whether lysosome-associated membrane protein 2 (LAMP2) is targeted by miR-207. The experiments were divided into four groups using the liposome transfection method (OP-LAMP2 group: co-transfected with miR-207 mimics and LAMP2 overexpression plasmid; EP group: co-transfected with mimics NC and null-loaded plasmid; siLAMP2 group: transfected with siLAMP2; and siLAMP2-NC group: transfected with siLAMP2-NC). TB infection was modeled using H37Ra-infected Ana-1 cells. The impact of LAMP2 on intracellular mycobacterial load and clearance of extracellular residual mycobacteria were assessed by tuberculosis colony-forming unit counting. Flow cytometry was used to assess the total apoptosis rate. Real-time fluorescent quantitative PCR was conducted to determine the relative expression of LAMP2, apoptosis genes, pyroptosis genes, and autophagy genes. Western blot analysis was performed to measure the relative expression of LAMP2 proteins, apoptosis proteins, pyroptosis proteins, and autophagy proteins. Results Dual luciferase reporter assay test showed that there was a targeting relationship between LAMP2 and miR-207. The transfection model was successfully constructed under real-time fluorescent quantitative PCR and Western blot statistical analysis, and microscopic observation. The infection model was successfully established under microscopic observation. Colony forming unit counting revealed that the number of colonies in the OP-LAMP2 group was lower than that in the EP group, while the number of colonies in the siLAMP2 group was higher than that in the siLAMP2-NC group. Flow cytometry assay revealed that the total apoptosis in OP-LAMP2 group was lower than that in EP group, and the total apoptosis in siLAMP2 group was higher than that in siLAMP2-NC group. Real-time fluorescence quantitative PCR and Western blot analysis revealed that the relative expression of apoptosis and pyroptosis-related proteins and genes in the control group was lower in the OP-LAMP2 group compared to the EP group, and higher in the siLAMP2 group compared to the siLAMP2-NC group. Real-time fluorescence quantitative PCR detected that the relative expression of autophagy positively regulated genes Microtubule-associated protein 1 light chain 3(LC3)and Beclin1 in the OP-LAMP2 group was higher in the OP-LAMP2 group compared to the EP group, and lower in the siLAMP2 group compared to the siLAMP2-NC group, while the relative expression of negatively regulated autophagy genes followed the opposite trend to that of autophagy positively regulated genes. The relative expression of autophagy-related proteins was consistent with the trend of autophagy genes. Conclusions miR-207 enhances macrophage apoptosis, cellular pyroptosis and inhibits autophagy, promoting survival of Mycobacterium tuberculosis by targeting the autophagy-related protein LAMP2, thus offering a novel therapeutic direction for tuberculosis.
Lysosomal-Associated Membrane Protein 2/metabolism* ; MicroRNAs/metabolism* ; Mycobacterium tuberculosis/physiology* ; Autophagy/genetics* ; Humans ; Macrophages/metabolism* ; Apoptosis/genetics* ; Tuberculosis/metabolism* ; Cell Line ; Pyroptosis/genetics*

The connection between tendons and bones is called the tendon bone connection. With the continuous improvement of national sports awareness, excessive exercises and the related intensity are prone to damage the tendon bone connection. Tendon bone healing is a complex repair and healing process involving multiple factors, and good tendon bone healing is a prerequisite for its physiological function. The complexity of tendon bone structure also poses great challenges to the repair of tendon bone injuries. In recent years, researches have found that stem cells, growth factors, macrophages, and other factors are closely related to the healing process of tendon bone injuries, among which macrophages play an important role in the healing process. The authors reviewed relevant research literature in recent years and summarized the role of macrophages in tendon bone healing, in order to provide new ideas and directions for treatment strategies to promote tendon bone healing.
Humans ; Macrophages/metabolism* ; Wound Healing ; Animals ; Tendons/physiology* ; Bone and Bones/injuries* ; Tendon Injuries

Pulmonary diseases, as a prevalent category of respiratory system disorders, have become a significant global public health concern. The increasing incidence of these diseases, caused by environmental pollution and occupational hazards, poses a substantial threat to human health and the overall quality of life. Mesenchymal stem cells (MSCs) are known for their remarkable immunomodulatory, anti-bacterial, and anti-apoptotic capabilities. Exosomes derived from MSCs, carrying a diverse array of proteins, lipids, nucleic acids, and other bio-active molecules, have demonstrated considerable therapeutic potential in treating pulmonary diseases, and have come to the forefront of medical research. This review summarized the therapeutic role of exosomes derived from various sources of mesenchymal stem cells in the context of pulmonary diseases, aiming to provide a robust foundation for their clinical application in diagnosis and treatment.
Exosomes/transplantation* ; Humans ; Mesenchymal Stem Cells/metabolism* ; Lung Diseases/therapy* ; Animals

Objective To investigate the clinical relevance and diagnostic or prognostic value of ST3β-galactoside α-2, 3-sialyltransferase 1 (ST3GAL1) in glioma and to confirm its role in promoting malignant phenotypes. Methods Using data from The Cancer Genome Atlas (TCGA) database, we analyzed the correlation between ST3GAL1 expression levels in glioma and clinical parameters to evaluate its diagnostic and prognostic value. The impact of ST3GAL1 on malignant phenotypes of glioma cells-including proliferation, cell cycle progression, apoptosis, and invasion was further validated through ST3GAL1 knockdown experiments. Results The expression level of ST3GAL1 was significantly higher in glioma tissues compared to healthy brain tissues and showed a strong correlation with clinical characteristics of glioma patients. Survival analysis and receiver operating characteristic (ROC) curve demonstrated that ST3GAL1 could serve as a potential diagnostic and prognostic biomarker for glioma. Knockdown of ST3GAL1 suppressed proliferation, invasion, and migration capabilities of glioma cell lines, and induced G1-phase cell cycle arrest. Conclusion ST3GAL1 promotes malignant phenotypes in glioma and plays a critical role in its malignant progression, suggesting its potential as a biomarker for glioma diagnosis and prognosis.
Humans ; Sialyltransferases/metabolism* ; Glioma/diagnosis* ; Cell Proliferation/genetics* ; Cell Line, Tumor ; Brain Neoplasms/enzymology* ; beta-Galactoside alpha-2,3-Sialyltransferase ; Disease Progression ; Prognosis ; Cell Movement/genetics* ; Apoptosis/genetics* ; Male ; Female ; Gene Expression Regulation, Neoplastic ; Biomarkers, Tumor/metabolism* ; Middle Aged

In hypoxic-ischemic brain damage (HIBD), the programmed cell death known as ferroptosis is significantly activated. Microglial cells demonstrate a high level of sensitivity to iron accumulation. Understanding how to regulate the dual role of microglia and transforming the microglial ferroptosis to a moderate and controllable process has considerable implications for the targeted treatment in HIBD. This paper serves as an overview of microglia-mediated ferroptosis in HIBD as a disease model. We discuss various aspects centered around microglia, including pathophysiological mechanisms, polarization and functions of microglia, molecular mechanisms of ferroptosis, signaling pathways, and therapeutic strategies. The review aims to provide a reference for studies of ferroptosis in microglia.
Microglia/physiology* ; Ferroptosis/physiology* ; Humans ; Animals ; Hypoxia-Ischemia, Brain/pathology* ; Signal Transduction

Objective To study the effect of Mycobacterium tuberculosis (Mtb) Pro-Pro-Glu-59 (PPE59) protein on the biological function of Mycobacterium smegmatis (Ms) and the regulation of host cell immune response. Methods PPE59 gene fragment was obtained by PCR amplification, cloned into pALACE, constructed into recombinant pALACE-PPE59 vector, and electro-transformed into Ms. Western blot was applied to analyse PPE59 expression and subcellular localization. The survival of Ms_Vec and Ms_PPE59 under low acid (pH=3 and pH=5) conditions and active surface pressure sodium dodecyl sulfate (SDS) conditions and their intracellular survival in macrophages were analyzed. ELISA was used to detect the cytokine (IL-1β, IL-6, IL-12, TNF-α and IL-10) expression levels of Ms_Vec and Ms_PPE59 infected macrophages. Results PPE59 protein localized to the cell wall of Ms can enhance the acid-resistance and anti-SDS effect of Ms, which is conducive to the survival of Ms in macrophages. PPE59 significantly decreased the secretion levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-12 and TNF-α), and promoted the secretion levels of anti-inflammatory cytokine (IL-10). Conclusion PPE59 enhances the survival ability of Ms under low acid and SDS pressure and promotes its intracellular survival by regulating the cytokine secretion levels.
Mycobacterium smegmatis/metabolism* ; Macrophages/metabolism* ; Cytokines/metabolism* ; Mycobacterium tuberculosis/metabolism* ; Bacterial Proteins/metabolism* ; Animals ; Mice ; Antigens, Bacterial/metabolism*

Alzheimer's disease (AD) remains a formidable challenge in modern healthcare, necessitating innovative approaches for its early detection and intervention. This study aimed to enhance the identification of individuals with mild cognitive impairment (MCI) at risk of developing AD. Leveraging advances in computational power and the extensive availability of healthcare data, we explored the potential of deep learning models for early prediction using medical claims data. We employed a bidirectional gated recurrent unit (BiGRU) deep learning model for predictive modeling of MCI progression across various prediction intervals, extending up to five years post-initial MCI diagnosis. The performance of the BiGRU model was rigorously compared with several machine-learning model baselines to evaluate its efficacy. Using a robust cross-validation methodology, the BiGRU emerged as the top-performing model, achieving an Area Under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.833 (95% CI: 0.822, 0.843), an Area Under the Precision-Recall Curve (AUC-PR) of 0.856 (95% CI: 0.845, 0.867), and an F1-Score of 0.71 (95% CI: 0.694, 0.724) for a five-year prediction interval. The results indicate that BiGRU, utilizing longitudinal claims data, reliably predicts MCI-to-AD progression over a lengthy interval following the initial MCI diagnosis, offering clinicians a valuable tool for targeted risk identification and stratification.

OBJECTIVE: To assess the risk of aristolochic acid (AA)-associated cancer in patients with AA nephropathy (AAN). METHODS: A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014. Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer. The primary endpoint was the incidence of liver cancer, and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014. RESULTS: A total of 337 patients diagnosed with AAN were included in this study. From the initiation of taking AA to the termination of follow-up, 39 patients were diagnosed with cancer. No cases of liver cancer were observed throughout the entire follow-up period, with urinary cancer being the predominant type (34/39, 87.17%). Logistic regression analysis showed that age, follow-up period, and diabetes were potential risk factors, however, the dosage of the drug was not significantly associated with urinary cancer. CONCLUSIONS No cases of liver cancer were observed at the end of follow-up. However, a high prevalence of urinary cancer was observed in AAN patients. Establishing a direct causality between AA and HCC is challenging.
Humans ; Retrospective Studies ; Incidence ; Carcinoma, Hepatocellular ; Liver Neoplasms/epidemiology* ; Kidney Diseases/chemically induced* ; Aristolochic Acids/adverse effects*

Objective To compare the differences in the clinical application of Sijunzi Decoction,a classical formula for tonifying qi,in ancient and modern literature,so as to provide a reference for its clinical application and research and development.Methods The clinical application of Sijunzi Decoction in ancient times was analyzed by retrieving the database of Zhong Hua Yi Dian(Collection of Traditional Chinese Medical Books),and the clinical application of Sijunzi Decoction in modern times was analyzed by retrieving the database of China National Knowledge Infrastructure(CNKI).Results In the record of ancient traditional Chinese medicine books,Sijunzi Decoction was indicated for the syndromes characterized by the pathogenesis of"deficiency of nutrient qi and defensive qi,and weakness of zang-fu organs",and was widely used to treat various diseases related to internal medicine,surgery,gynecology and pediatrics,including dysentery,consumptive disease,diarrhea,jaundice,smallpox,metrorrhagia and carbuncle.Moreover,Sijunzi Decoction was used for the management of patients who was weakness due to chronic diseases,elderly and insufficiency of qi,or at the late stage of exogenous cold disease,cholera,and malaria.In the modern clinical practice,Sijunzi Decoction was indicated for digestive system diseases,surgical diseases,tumor-related diseases,pediatric diseases,gynecological diseases,respiratory diseases and hepatobiliary diseases,in particular for chronic gastritis,adverse reactions related to radiotherapy and chemotherapy for tumors,postoperative period of cancer and diabetes mellitus during pregnancy.Conclusion The analysis of ancient and modern literatures indicated that the indications of Sijunzi Decoction is expanded from the predominated spleen-stomach system diseases(digestive system diseases)in antient times to multiple system diseases such as surgical diseases,tumor-related diseases,pediatric diseases,gynecological diseases,respiratory diseases and hepatobiliary diseases in modern times.And the pathogenesis of the indications of Sijunzi Decoction is characterized by the"deficiency of nutrient qi and defensive qi,and weakness of the zang-fu organs".