Lishui Maternity and Child Health Care Hospital

Abstract Background: RJBC 1501 (NCT02455141) is a prospective phase III study to compare the efficacy and safety of adjuvant epirubicin plus cyclophosphamide (EC) followed by taxanes (T) versus same regimen plus carboplatin (EC-TCb) in early-stage triple negative breast cancer (TNBC). Methods: Patients with node positive or node negative (with tumor size ≥1.0cm) TNBC who received definitive surgery were randomized 1:1 to receive EC-T or EC-TCb. Taxanes consisted of either weekly paclitaxel for 12 doses or docetaxel every 3 weeks for 4 cycles. Carboplatin was given weekly (AUC 2) for 12 doses or every 3 weeks (AUC 5-6) for 4 cycles, concurrent with taxanes. The primary endpoint was disease-free survival (DFS) in the intention-to-treat (ITT) population. Secondary endpoint includes distant DFS (DDFS), overall survival (OS), and safety. Results: Between March 2016 and March 2023, 786 patients were randomized (EC-T: n = 391; EC-TCb: n = 395). Baseline characteristics were balanced: median age ≤50 years (49.6%), T1 stage (46.6%), node-negative (72.3%). A majority of patients (76.5%) received 3-weekly docetaxel. After a median follow up of 4.52 (IQR 2.83 to 6.06) years, 103 events were reported: 62 in the EC-T group and 41 in the EC-TCb group. Addition of carboplatin significantly improved DFS (hazard ratio [HR], 0.66; 95% CI, 0.44 to 0.97, P = 0.034), with 3-year DFS of 89.8% (95%CI 86.8 to 92.9%) for EC-T and 93.1% (95%CI 90.5 to 95.7%) for EC-TCb. EC-TCb regimen was also associated with a superior DDFS (HR, 0.61; 95% CI, 0.38 to 0.98, P = 0.040) and OS (HR, 0.39; 95% CI 0.16 to 0.94, P = 0.029) compared to EC-T treatment. Grade 3-4 adverse events were more frequent among EC-TCb arm (49.9%) than EC-T arm (38.7%), primarily driven by higher rates of neutropenia (47.0% vs 37.8%) and thrombocytopenia (4.5% vs 0%). Other grade 3-4 toxicities were comparable between groups. Conclusion: Adding carboplatin to adjuvant EC-T chemotherapy significantly improves DFS, DDFS, and OS in patients with early-stage TNBC. While additional carboplatin treatment was associated with increased hematologic toxicity, no new safety signals emerged. Citation Format: X. Chen, J. Huang, H. Shi, J. Zhu, W. Wu, G. Ye, Q. He, Y. Shi, A. Zhang, X. Xie, X. Wang, X. Chen, W. Wu, J. Wu, Z. Li, Z. Li, Y. Dai, W. Ren, Q. Shao, Y. Chen, Y. Zeng, M. Pegram, K. Shen. Adjuvant epirubicin plus cyclophosphamide followed by taxanes with or without carboplatin for early stage triple-negative breast cancer (RJBC 1501): a randomized controlled phase III trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF2-03.

Interleukin-15 receptor alpha (IL15RA) demonstrates critical regulatory function in oncogenesis and immunomodulation across various malignancies. However, the role of IL15RA in cancers, such as Clear Cell Renal Cell Carcinoma (ccRCC) remains unclear. Therefore, integrated pan-cancer analysis and mechanism investigation assays are essential for IL15RA-directed therapeutic strategy optimization in ccRCC. The comprehensive pan-cancer analysis reveals IL15RA as a plausible diagnostic and prognostic biomarker, as well as a promising immunotherapeutic target across various cancers, particularly ccRCC. IL15RA promotes ccRCC metastasis based on the data of the investigation. Mechanistically, STAT1 binds to IL15RA promoter region, thereby enhancing IL15RA mRNA expression, while METTL3 modulates RNA m6A methylation patterns to stabilize IL15RA transcription. Furthermore, IL15RA potentiates metastasis via NF-κΒ/ZEB1 axis in ccRCC. Drug sensitivity profiling further indicates that IL15RA expression increases sensitivity to chemotherapeutic agents in ccRCC patients. The findings demonstrate that IL15RA emerges as a critical prognostic indicator and immunotherapeutic biomarker particularly in ccRCC. Our findings underscore the necessity for comprehensive mechanistic studies to elucidate IL15RA’s roles and are beneficial for advancing targeted therapeutic strategies in oncological interventions.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-21947-x.

Doxorubicin(DOX), which is a first-line broad-spectrum chemotherapeutic agent remains constrained clinical efficacy by dose-dependent cardiotoxicity, multidrug resistance, and systemic toxicity. Recent advancements in nanocarrier-based drug delivery systems have demonstrated remarkable potential to enhance tumor-specific accumulation, modulate drug release kinetics, and mitigate off-target effects through innovative engineering strategies. Contemporary nanocarrier researchers have expanded beyond conventional efforts to enhance tumor targeting and optimize drug release kinetics, which emphasizes the pathophysiological roles of the tumor microenvironment (TME) in mediating oncogenesis, neoplastic progression, and therapeutic resistance. This review emphasizes two pivotal strategies: (1) Structural innovation in tumor-targeting nanocarrier design through stimuli-responsive release mechanisms and molecular recognition targeting; (2) Therapeutic reprogramming of the TME via combinatorial extracellular matrix modulation. Through systematic analysis of 2019-2022 literatures from major scientific databases, this review synthesizes the advances in DOX-loaded nanocarriers targeting TME reprogramming and immunomodulation, and evaluates novel delivery platforms that overcome DOX's dose-limiting toxicity while potentiating antitumor efficacy.

BackgroundPrevious in vitro studies indicated that 25 hydroxyvitamin D [25(OH)D] might contribute to the modulation of anemia parameters while epidemiological evidences were scarce in children. We explored the associations of 25(OH)D with hemoglobin (Hb) and other anemia parameters (mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration [MCHC], and serum ferritin [SF]) in children.MethodsA cross-sectional study involving 10,227children (mean age 14.6 months) in Nantong, China, was carried out. Serum 25(OH)D, MCV, MCHC, and SF concentrations were measured.ResultsAfter adjustment for the potential covariates, serum 25(OH)D was positively associated with anemia parameters (quartile [Q] 4 vs. Q1: 127.304 vs. 78.982 g/L for Hb; 83.957 vs. 66.264 fL for MCV; 334.551 vs. 208.368 g/L for MCHC; 34.277 vs. 32.807 ng/mL for SF). Similar results were shown in the stratified analyses by gender. Consistently, a higher 25(OH)D was found to be related with a lower risk of anemia (ORQ4 vs. Q1: 0.06, 95% CIQ4 vs. Q1: 0.05, 0.07) in multi-variable analysis among total populations. Additionally, the “25(OH)D–anemia parameters (Hb, MCV, and MCHC)” and “25(OH)D–anemia” associations were mediated by hsCRP.ConclusionsIn general, our findings provided further support for the anti-anemia effects of 25(OH)D in Chinese children. Further research is warranted to replicate these results in different populations and in experimental settings.

SummaryBackgroundPelvic floor surface electromyography (sEMG) is widely used to evaluate and treat pelvic floor dysfunctions (PFDs). Based on sEMG, the Glazer protocol was developed over 20 years ago with a limited sample size, making it challenging to accurately diagnose PFDs across diverse populations and conditions. This study aims to establish a multidimensional database for monitoring pelvic floor sEMG, derive more reasonable reference ranges for sEMG parameters, and achieve accurate diagnosis of PFDs through artificial intelligence (AI).MethodsIn this population-based, multicenter, cross-sectional study, we recruited 1605 participants from 21 centres across China, collected pelvic floor sEMG data, and established a multidimensional sEMG database. Based on the database, we developed an AI-Diagnostician-PFD diagnostic model, which leverages AI to derive AI-Reference ranges for sEMG parameters and diagnose PFDs. Data from 15 centres were divided into a training dataset (60%) and a test dataset (40%), while data from 6 additional centres were used to form an independent validation dataset. The proportions of normal and abnormal samples were consistent across the 15 and 6 centres, ensuring balanced representation. Additionally, both datasets encompassed diverse geographical regions, enhancing the model's generalizability. The diagnostic performance of the AI-Diagnostician-PFD model was evaluated on both the internal test dataset and the external validation dataset.FindingsIn the external validation dataset, the area under the receiver operating characteristic curve (AUC) of the AI-Reference ranges was 11% higher than that of the Glazer standard. Specifically, the AUC values for the AI-Reference ranges on the internal and external validation datasets were 0.81 (95% CI: 8.13 × 10−1, 8.16 × 10−1) and 0.79 (95% CI: 7.90 × 10−1, 7.94 × 10−1), respectively, surpassing the AUC values of the Glazer standard of 0.76 (95% CI: 7.56 × 10−1, 7.59 × 10−1) and 0.68 (95% CI: 6.74 × 10−1, 6.78 × 10−1). Furthermore, the AI-Diagnostician-PFD model demonstrated superior diagnostic performance for PFDs, achieving an AUC 1% higher than other classical machine learning and deep learning models.InterpretationThe performance of the reference interval derived by AI surpassed that of the Glazer standard. Upon publication of this study, the AI-Diagnostician-PFD model for PFD prediction will be provided free via software on machines. Implementing this algorithm in clinical practice can enhance individual PFD diagnosis and improve population-level health outcomes.FundingThis study was supported by grants from the 10.13039/501100012166National Key R&D Program of China: The Establishment of a Comprehensive Network for PFD Prevention, Rehabilitation, Pelvic Floor Surgery and Related Complications (2021YFC2701300), Perception and Analysis of the Situation of Major Infectious Disease Outbreaks Based on Internet Big Data (2021ZD0111202), Research on New Models for Forecasting Major Infectious Diseases and Policy Evaluation (2021ZD0111205); Beijing Natural Science Foundation (7212073), National High-Level Hospital Clinical Research Funding (2022-PUMCH-B-087) and the 10.13039/501100005150Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2021-I2M- C&T-B- 021).

A short peptide derived from the occludin protein regulates tight junctions (TJ) of the blood–testis barrier and impairs germ cell development. However, the mechanism behind how this peptide regulates TJ and induces cell apoptosis remains unclear. In the present study, an animal model with induced TJ disruption via the short peptide was used to evaluate its impact on spermatogenesis. Here, we demonstrate that the short peptide promoted the infiltration of immune cells into the testicular interstitial tissue, accompanied by upregulation expression of the pro‐inflammatory factors interleukin‐6 and tumor necrosis factor‐α. Moreover, mitochondrial fragmentation and mitophagy were upregulated in Sertoli cells and Leydig cells. Consistently, terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed extensive apoptosis in the testes during spermatogenesis. Notably, the severity of these disruptions began to attenuate after 27 days, although full functional recovery was not observed. Our findings reveal a novel mechanism wherein peptide‐induced immune dysregulation and mitochondrial dysfunction synergistically impair spermatogenesis, potentially via microenvironmental perturbation of the TJ. Overall, these findings could hold valuable insights for the development of non‐hormonal male contraceptives.

BackgroundTesticular aging has profound effects on spermatogenesis, sperm function, and the spermatogenic microenvironment, contributing to reduced male fertility. However, the precise molecular mechanisms by which mitochondria influence spermiogenesis during aging still remain largely unclear.MethodsVha68-3 KO flies were generated using the CRISPR/Cas9 technique. Testicular phenotypes and functions were mainly observed through immunofluorescence staining and transmission electron microscopy. Multi-omics study was mainly conducted through single-cell RNA sequencing and transcriptome–metabolomics association analysis. Vha68-3 binding proteins were identified via liquid chromatography–tandem mass spectrometry. The therapeutic potential of modulating mitochondrial metabolism for testicular aging mainly relied on the dietary intake of related compounds in fruit flies.ResultsIn this study, we identified Vha68-3, a testis-specific subunit of the V-type adenosine triphosphate (ATP) synthase, predominantly localized in the tails of elongated spermatids, as a key age-related regulator of male fertility and spermatid elongation in Drosophila testes. Crucially, Vha68-3 deficiency impaired mitochondrial homeostasis in elongated spermatids during testicular aging. Through a multi-omics approach, including single-cell transcriptomics, protein interaction mapping of Vha68-3, and transcriptome–metabolome integration, we identified pyruvate metabolism as a critical pathway disrupted by Vha68-3 deficiency. Moreover, dietary supplementation with pyruvate (PA), S-lactoylglutathione (SLG), and phosphoenolpyruvate (PEP) effectively alleviated mitochondrial dysfunction and testicular aging linked to Vha68-3 deficiency.ConclusionsOur findings uncover novel mechanisms by which mitochondrial metabolism regulates spermatid elongation and propose potential therapeutic strategies to combat mitochondrial metabolic disorders in aging testes.

Gestational diabetes mellitus (GDM) poses serious health risks to both mothers and fetuses. However, effective tools for identifying GDM are lacking. This study, based on a Chinese cohort, aims to construct and compare the predictive performance of traditional logistic regression (LR) and six advanced machine learning (ML) models, thereby aiding in the early identification and intervention of GDM. This retrospective study utilized medical examination data from 956 singleton pregnant women collected between January and December 2023 from ten maternal and child health hospitals in Pinghu City. We employed receiver operating characteristic curves and precision-recall curves to assess the predictive performance of the models. Decision curve analysis (DCA) was used to evaluate clinical utility, while calibration curves and Hosmer-Lemeshow (HL) tests were applied to assess the calibration of each model. The 956 participants were randomly divided into a training set and a validation set at a 3:1 ratio. We identified 13 features through Spearman correlation analysis and the Boruta algorithm to construct the models. The LR model exhibited the best AUC at 0.787 (0.723-0.85), outperforming the seven other ML models including RF at 0.776 (0.711-0.841). Furthermore, the LR model showed good calibration and clinical utility. Although ML has tremendous potential, in predicting the occurrence of GDM based on common early pregnancy data, the ML models did not completely outperform the traditional LR model. Simpler, traditional models may be more effective than complex ML approaches.

Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.