Preeclampsia (PE) is a leading cause of maternal morbidity and mortality, but the coordinated dysregulation between the placental unit and the maternal systemic immune response remains incompletely understood. An integrated multi-omics approach is required to decipher these cross-tissue interactions. We performed an integrated analysis of bulk transcriptome data from 810 pregnancies (299 placental tissues and 511 blood samples). Additionally, to gain mechanistic insights at cellular resolution, we analyzed single-cell RNA sequencing (scRNA-seq) data from maternal endometrial biopsies (from non-pregnant women with a history of PE or Normal, n = 21) and peripheral blood mononuclear cells (PBMCs, n = 10). Analytical methods included differential expression analysis, pathway enrichment, machine learning-based predictive modeling, and cell–cell communication inference. Analysis of bulk transcriptomes from placental and blood specimens identified 25 core genes consistently associated with PE. A Random Forest model constructed with these genes demonstrated high predictive accuracy (AUC > 0.96 in both tissue and blood) and was validated in an independent cohort (AUC = 0.775). To explore the cellular basis of this signature, we turned to scRNA-seq data. Analysis of maternal endometrium and PBMCs identified a reconfigured immune microenvironment, characterized by an increased proportion of LYZ + monocytes in endometrium from women with a history of PE. A key finding was the significant downregulation of the coagulation factor F13A1 within monocyte/macrophage lineages across both bulk and single-cell datasets. Cell–cell communication analysis further suggested that monocytes/macrophages may regulate immune and endothelial cells through dysregulated COMPLEMENT and GALECTIN signaling pathways. Our study defines a robust, placenta-blood based gene signature for PE. Exploratory analysis of maternal endometrial and immune cells at single-cell resolution provides preliminary evidence that monocyte/macrophage dysfunction, including F13A1 downregulation, may be a pervasive feature of PE pathophysiology, observable even in maternal tissues beyond the placenta. These findings highlight the potential of cross-tissue biomarkers and justify further investigation into the systemic role of myeloid cells in PE.
Current body surface area (BSA)-based dosing of liposomal paclitaxel (L-PTX) fails to account for substantial interpatient variability in drug exposure, leading to inconsistent therapeutic outcomes. This study investigated the relationships between L-PTX pharmacokinetic exposure (quantified as time above threshold concentration [Tc>0.05]), CYP2C8 metabolic activity, and clinical outcomes in gynecological oncology patients receiving platinum-based combination therapy with L-PTX. We conducted a study of 85 patients with gynecological tumors receiving platinum-based combination therapy with L-PTX (September 2020–January 2023). Plasma concentrations of paclitaxel and its metabolite 6α-hydrpaclitaxel (6α-OHP) were measured 20–22 h post-infusion using validated ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) methods. Tc>0.05 and CYP2C8 activity (6α-OHP/PTX ratio) were calculated. Clinical outcomes were assessed on the basis of progression-free status, with disease recurrence or progression recorded during follow-up. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) grading. L-PTX Tc>0.05 was normally distributed within the range of 13.49–41.30 h, with up to a threefold difference among patients. CYP2C8 metabolic enzyme activity showed a non-normal distribution, ranging from 0.00469 to 0.08830, with up to an 18-fold difference. Correlation analysis revealed that L-PTX Tc>0.05 and CYP2C8 metabolic enzyme activity were significantly correlated with clinical efficacy and neutropenia. The results suggest a potential therapeutic range for L-PTX Tc>0.05 in patients with gynecological tumors of approximately 21–29 h. BSA-based L-PTX dosing inadequately addresses pharmacokinetic variability. We demonstrate that Tc>0.05 and CYP2C8 activity significantly influence treatment outcomes and toxicity, supporting the need for personalized dosing strategies. The suggested target range (approximately 21–29 h) warrants further validation in prospective clinical trials before it can be considered for clinical application.
Abstract Background Patients with hepatocellular carcinoma (HCC) have an unmet need for new therapies that improve survival. This phase II trial investigated the efficacy and safety of ociperlimab and tislelizumab plus BAT1706 (a bevacizumab biosimilar) in patients with first-line HCC. Methods In this phase II, multicenter, randomized, multi-arm, open-label trial, patients with advanced HCC received ociperlimab and tislelizumab plus BAT1706 (Arm A) or tislelizumab plus BAT1706 (Arm B). The primary objective was to evaluate efficacy using objective response rate (ORR) assessed by the investigator per RESIST v1.1 for Arms A and B. Results 94 patients were randomized to Arm A (N = 62) and Arm B (N = 32). Confirmed ORR (95% confidence interval) was 37.1% (25.2–50.3) for Arm A and 40.6% (23.7–59.4) for Arm B. In Arms A and B, respectively, 90.3% and 80.6% of patients experienced treatment-related treatment-emergent adverse events (TEAEs), 59.7% and 32.3% experienced Grade ≥ 3 treatment-related TEAEs and 22.6% and 9.7% experienced treatment-related TEAEs leading to treatment discontinuation. Immune-mediated adverse events were reported in 50.0% of patients in Arm A and 45.2% of patients in Arm B. Infusion-related reactions occurred in a single patient in Arm A. Conclusion In patients with advanced HCC, tislelizumab plus BAT1706 demonstrated promising ORR, while adding ociperlimab was not associated with improved efficacy. The safety profile of ociperlimab and tislelizumab plus BAT1706 was tolerable and manageable, with no new safety signals identified. Trial registration ClinicalTrials.gov: NCT04948697 (September 20, 2021).
Triple-negative breast cancer (TNBC) poses a formidable clinical challenge due to its aggressive behavior and limited therapeutic avenues. Here, we delineate a novel pathway wherein BPHL governs R-loop homeostasis to sustain cancer stem cell (CSC) stemness in TNBC. Through single-cell RNA sequencing (scRNA-seq) of 26 breast cancer samples, we identified low R-loop scores as a defining feature of TNBC CSCs, marked by elevated chromosomal instability and stemness signatures. Extensive cohort analysis further confirmed that this low R-loop profile significantly correlates with poor patient prognosis and advanced tumor staging. Bioinformatics interrogation pinpointed BPHL as the pivotal regulator, a finding corroborated by the strong positive correlation between BPHL expression and lactylation markers in clinical specimens. Functional studies across multiple TNBC models revealed that BPHL overexpression expanded the CSC compartment, bolstered sphere formation, and accelerated tumor growth in vitro and in vivo. Consistent with the low R-loop phenotype, genes enriched in low R-loop TNBC cells and CSCs were linked to cell cycle progression, DNA replication/checkpoint control, and p53-associated pathways.Mechanistically, BPHL engages POLR2A, curtailing its lactylation while augmenting BARD1-mediated ubiquitination to resolve R-loops and enable β-catenin nuclear translocation, thereby perpetuating Wnt signaling. Beyond intrinsic tumor programs, low R-loop states were also associated with enhanced intercellular communication (notably MIF/MK signaling) and elevated immune checkpoint gene expression (e.g., PDCD1, CTLA4, TIGIT, LAG3). Intriguingly, in vivo BPHL depletion curbed tumorigenesis-an effect partially mitigated by RNase H overexpression but reinstated by β-catenin blockade. These insights position BPHL as a compelling target for eradicating TNBC CSCs.
OBJECTIVE:To investigate whether the reliability of telesurgery is non-inferior to that of standard local surgery in patients undergoing urological robotic operations. DESIGN:Multicentre, non-inferiority, randomised controlled trial. SETTING:Five hospitals in China from December 2023 to June 2024. PARTICIPANTS:Patients scheduled to undergo radical prostatectomy or partial nephrectomy. INTERVENTIONS:Patients were randomly assigned 1:1 to undergo telesurgery or local surgery. MAIN OUTCOME MEASURES:The primary outcome was the probability of success of surgery, determined by the medical team on the basis of pre-established criteria. The pre-specified non-inferiority margin was an absolute reduction in probability of 0.1. Thirteen clinical secondary outcomes were associated with the operation and early recovery, and one secondary outcome related to the workload of the medical team. Four technical secondary outcomes for the surgical system were also explored, including network latency, display latency, frame loss during telesurgery, and system malfunction. The participants were followed up at four and six weeks postoperatively for the secondary outcomes of recovery and complications. RESULTS:A total of 72 participants were enrolled in the study and randomised 1:1 to the telesurgery group and the local surgery group for the intention-to-treat set. The median age of patients was 61.0 (interquartile range 57.5-68.0) years in the telesurgery group and 65.0 (56.5-70.0) years in the local surgery group. Telesurgery was not inferior to local surgery in terms of the probability of surgical success in the intention-to-treat population, accounting for clustering by surgeon (success probability difference 0.02 (95% credible interval -0.03 to 0.15) with bayesian posterior probability of 0.99 for non-inferiority). The telesurgery system was stable with a distance from 1000 km to 2800 km, a mean round trip network latency of 20.1-47.5 ms, and frame loss of 0-1.5 per telesurgery. Secondary outcomes, including operative basic data, complications, early recovery, oncological outcome, and medical team workload, did not differ substantially between the two groups. CONCLUSIONS:The reliability of telesurgery was non-inferior to that of local robotic surgery according to the non-inferiority margin of a 0.1 reduction in success probability. TRIAL REGISTRATION:ChiCTR.org ChiCTR2300077721.
