Objective: To establish the recommended dose (MTD) and assess the safety and tolerability of lobaplatin (LBP) combined with paclitaxel for subsequent clinical development in platinum-sensitive recurrent ovarian epithelial carcinoma (PSROC), with antitumor activity evaluated as an exploratory endpoint. Methods: Twelve patients were enrolled in three LBP dose cohorts (25, 30, 35 mg/m2), with paclitaxel administered at a fixed dose of 175 mg/m2. MTD was established by a 3 + 3 escalation design based on the occurrence of dose-limiting toxicities (DLTs) within Cycle 1. Safety evaluation was performed with CTCAE v5.0 criteria while pharmacokinetic (PK) analysis employed HPLC-MS/MS. Exploratory antitumor activity was assessed using objective response rate (ORR) per RECIST v1.1, progression-free survival (PFS), and overall survival (OS). Results: The MTD was established at 30 mg/m2, following the occurrence of two DLTs (Grade 4 neutropenia lasting > 7 days) at the 35 mg/m2 dose level. The regimen demonstrated a 50% ORR (1 CR, 5 PR) and a 100% disease control rate. Median PFS was 7.0 months (95% CI:5.3-NA) with a median OS of 21.7 months (95% CI:7.3-NA). Grade 3-4 hematologic toxicities were neutropenia (100%), thrombocytopenia (41.7%), and anemia (33.3%) that were manageable with supportive care. Non-hematologic toxicities were primarily Grade 1-2 (nausea/vomiting 25%, neuropathy 16.7%). PK analysis demonstrated dose-proportional exposure (AUC slope 1.02) and rapid renal clearance, with 68.5% of the administered dose excreted in urine within 24 h. Conclusion: The LBP-TAX regimen demonstrated manageable toxicity and established an MTD of 30 mg/m2 in PSROC. Observed antitumor activity in this small phase I cohort are exploratory and warrant confirmation in larger, appropriately powered studies. A Phase I Dose-Escalation Study of Lobaplatin Combined with Paclitaxel in Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma: Preliminary Safety and Tolerability Supporting Clinical Trial Dosing.

ObjectivesTo investigate the mechanism underlying the inhibitory effect of epigallocatechin gallate (EGCG) on shear-induced platelet aggregation(SIPA) and activation.MethodsUsing an 80% eccentric stenotic microfluidic chip, we simulated physiological (1500 s-1) and pathological high shear rates (4500 s-1 and 9000 s-1). Whole blood samples preincubated with EGCG (25-200 μM) were perfused through the chips. SIPA was quantified by real-time image analysis, and platelet activation was measured by flow cytometry for CD62P (P-selectin) and PAC-1 expression. The potential mechanism was probed using Ristocetin-induced activation.ResultsEGCG demonstrated a potent, concentration-dependent inhibition of SIPA and platelet activation at both 4500 s-1 and 9000 s-1, evidenced by reduced platelet aggregate coverage and lower CD62P/PAC-1 expression. The inhibitory effect was confirmed to be mediated through the von Willebrand factor (vWF)-GPIbα pathway, as EGCG also suppressed Ristocetin-induced platelet activation.ConclusionThis study offers systematic microfluidic evidence that EGCG exerts a concentration-dependent, selective inhibition of pathological SIPA and activation at 4500 s-1 and 9000 s-1, while exerting no significant effect on platelet aggregation function under physiological shear rate (1500 s-1). By targeting the vWF-GPIbα axis without affecting coagulation, EGCG emerges as a promising prototype for developing novel, bleeding-risk-free antiplatelet therapies.

Objective:Accurately predicting the prognosis of cervical cancer in younger patients is increasingly important due to the rising incidence of the disease in China and the growing number of cases among individuals under 50. This study aimed to develop a nomogram to predict overall survival (OS) in cervical cancer patients under 50 in southwest China. Methods:Clinicopathological and follow-up data for cervical cancer patients under 50 were prospectively collected as part of an ongoing longitudinal cohort study at Chongqing University Cancer Hospital between January 1, 2015, and May 31, 2019. A training cohort (n = 703) and a validation cohort (n = 301) were randomly selected. Variables associated with OS were assessed using a Cox regression model. Multivariate analysis was used to construct the nomogram and identify independent prognostic factors. The model's performance was evaluated using decision curve analysis (DCA), calibration curves, area under the receiver operating characteristic curve (AUC-ROC), and the concordance index. Results:The final model identified pathology, International Federation of Gynecology and Obstetrics (FIGO) staging, treatment, β2-microglobulin, neutrophil-lymphocyte ratio (NLR), and albumin as independent risk factors for OS in patients under 50. The concordance index for OS was 0.818 in the training cohort and 0.747 in the validation cohort. Calibration curves in both cohorts showed strong agreement between predicted and observed survival probabilities. In the training cohort, AUCs for 1-, 3-, and 5-year OS were 0.851, 0.847, and 0.816, respectively; in the validation cohort, they were 0.810, 0.733, and 0.730. Compared to the FIGO staging system, the nomogram demonstrated superior predictive accuracy and net benefit, as shown by the net reclassification index (NRI) and DCA. Conclusion:The nomogram provides a reliable tool for predicting overall survival in cervical cancer patients under 50, supporting more personalized treatment planning.

Retinal thrombotic diseases, a major cause of vision impairment, lack effective treatments that directly resolve vascular occlusion. To address this challenge, we developed a novel multifunctional nanoplatform for targeted thrombolysis: PLGA-PFP-rtPA nanoparticles modified with the fibrin-targeting peptide CREKA (PPrC NPs). The nanoparticles were successfully fabricated with a spherical morphology, a mean size of 289 ± 4.1 nm, and a zeta potential of -13.6 ± 1.1 mV, indicating good stability.In vitrothrombolysis assays demonstrated that PPrC NPs, combined with low-intensity ultrasound (US), exhibited significantly superior thrombolytic efficacy compared with controls (P< 0.05), owing to a synergistic effect of fibrin targeting, US-responsive drug release, and phase-transition enhancement. Cytotoxicity assays on human retinal microvascular endothelial cells confirmed high biocompatibility, with cell viability exceeding 90% at concentrations up to 1000 µg ml-1. Furthermore, comprehensive hemocompatibility evaluations, including hemolysis, coagulation function, complement activation (C3a), and platelet activation, revealed no adverse effects within the therapeutically relevant concentration range (⩽800 µg ml-1). Collectively, these findings indicate that the CREKA-modified nanoplatform provides a safe and effective strategy for targeted thrombolysisin vitro, presenting a promising foundation for developing minimally invasive therapies for retinal thrombotic diseases.

Objective To investigate the effect of polyphyllin I on MCF-7 spheroids enriched with cancer stem cells and to preliminarily observe its effect on the hybrid epithelial-mesenchymal transition （EMT） state and its regulatory role on cell stemness. Methods MCF-7 spheroids were cultured under serum-free，non-adherent conditions.Cell viability，invasion，and key protein expression were assessed through the cell counting kit-8 assay，Transwell assay，and Western blot，respectively.The CD44+/CD24-/low cell population was analyzed by flow cytometry. Results The MCF-7 spheroids exhibited high proliferative and invasive capacities，co-expressing the epithelial marker E-cadherin and the mesenchymal marker vimentin，which is indicative of a hybrid EMT state and high stemness.Polyphyllin I treatment significantly suppressed the viability and invasion of MCF-7 spheroids.From a mechanism perspective，polyphyllin I downregulated the E-cadherin/vimentin ratio，significantly reduced the levels of stemness-associated proteins CD44 antigen，aldehyde dehydrogenase 1 family member A1，as well as the ratio of phosphorylated signal transducer and activator of transcription 3 to total signal transducer and activator of transcription 3.Simultaneously，polyphyllin I decreased the proportion of CD44+/CD24-/low cells.No significant changes were observed in key proteins of the intrinsic apoptosis pathway. Conclusions Polyphyllin I reshapes the hybrid EMT state in MCF-7 spheroids，which is accompanied by the disruption of their high stemness equilibrium.This compound may reduce cellular stemness through the EMT remodeling process，thereby exerting antitumor effects，and this mechanism is independent of the intrinsic apoptosis pathway.

Precise monitoring of platelet function is fundamental to the effective management of cardiovascular diseases, yet conventional testing methodologies often overlook the influence of physiological fluid dynamics. Herein, we introduce and evaluate a microfluidics fabricated from 3D-Printed mold-based technique enabling the dynamic visualization and quantitative analysis of platelet adhesion and aggregation under simulated in vitro flow conditions. Using our model, we demonstrate that platelet aggregation is highly dependent on shear rate, with higher flow velocities leading to significantly larger and denser aggregates. Furthermore, at a single, physiologically relevant flow rate, we assessed the efficacy of common antiplatelet drugs-tirofiban, ticagrelor, and aspirin-revealing distinct potency hierarchies in their ability to inhibit platelet aggregation. Our demonstration of shear-sensitive platelet responses underscores a critical requirement: the evaluation of antiplatelet drugs must be conducted within a physiologically relevant hemodynamic context. Therefore, this microfluidic model represents a rapid, efficient, and powerful tool, not only for fundamental studies of platelet function but also as a promising platform for the personalized analysis of drug efficacy under simulated flow conditions.

This study aimed to systematically evaluate the antiplatelet activity of dihydromyricetin (DHM) and comprehensively investigate its effects on coagulation function within its therapeutically relevant concentration range. Using in-vitro experiments, we employed a panel of standard assays to assess the effects of DHM on platelet activation and aggregation induced by various agonists [adenosine diphosphate (ADP), arachidonic acid (AA), and collagen (COL)], as well as on agonist-independent adhesion and aggregation. Simultaneously, multidimensional techniques, including conventional coagulation tests, thromboelastography (TEG), and whole-blood dynamic coagulation analysis, were used to systematically evaluate the impact of DHM on the coagulation cascade and overall hemostatic dynamics. The results showed that DHM significantly inhibited platelet activation and aggregation in a concentration-dependent manner and effectively prevented their spontaneous adhesion and aggregation. Crucially, within the concentration range that exerted effective antiplatelet effects, DHM did not significantly affect any of the tested coagulation parameters, and no cytotoxicity was observed. These in-vitro findings suggest that DHM is a platelet-specific inhibitor, exerting potent antiplatelet effects while not interfering with normal physiological coagulation processes. Therefore, DHM shows potential as an antithrombotic candidate pending in-vivo studies with a potentially low risk of bleeding, providing crucial experimental evidence and a new direction for the development of safer antithrombotic strategies.

To investigate the concentration- and shear-dependent effects of ethanol on platelet adhesion, activation, and aggregation under pathologically high shear stress mimicking arterial stenosis, and to determine whether its primary target is platelet function or the coagulation cascade. This study aims to resolve the paradoxical relationship between alcohol consumption and cardiovascular risk. Using a validated microfluidic chip platform, we established in vitro models simulating normal vasculature (venous shear: 300 s⁻¹; arterial shear: 1500 s⁻¹) and 80

Ginsenoside Rg1, a key bioactive component of Panax ginseng, is recognized for its cardiovascular protective effects, yet its role in modulating platelet activation under high shear stress remains incompletely understood. This study aimed to systematically evaluate the in vitro effects and underlying mechanisms of Rg1 on platelet aggregation under high shear stress using a microfluidic chip system. In this study, blood flow environments at venous (300 s−1), arterial (1500 s−1), and pathological arterial (5000 s−1) shear rates were simulated using microfluidic chips. The effects of Rg1 (0–1000 μM) on platelet aggregation and activation were assessed via fluorescence imaging, flow cytometry (measuring P-selectin and GP IIb/IIIa activation), and Western blot analysis of intracellular signaling pathways. Coagulation parameters (APTT, PT, TT) and blood compatibility were also evaluated. Our results showed that Rg1 concentration-dependently inhibited platelet aggregation across all tested shear rates, showing particularly pronounced suppression under high shear stress (5000 s−1). Mechanistically, Rg1 significantly reduced P-selectin expression and GP IIb/IIIa activation. Western blot analysis revealed that Rg1 exerted its antiplatelet effects primarily by suppressing the PI3K/AKT and ERK1/2 signaling pathways and enhancing VASP phosphorylation, while exhibiting limited direct inhibitory effects on the Syk/PLCγ2 pathway. Notably, Rg1 did not significantly alter standard coagulation parameters or cause hemolysis within the tested concentration range. In conclusion, ginsenoside Rg1 demonstrated potent concentration-dependent inhibition of platelet activation and aggregation under high shear stress in this in vitro study. Its mechanism involves the multi-target modulation of key intracellular signaling pathways (PI3K/AKT, ERK1/2, and PKG/VASP). Furthermore, Rg1 exhibited favorable blood compatibility without impairing coagulation function in vitro. These findings suggest that Rg1 is a promising candidate warranting further preclinical investigation for targeted intervention in arterial thrombosis, although its therapeutic efficacy and safety require validation in vivo. Ginsenoside Rg1 attenuates platelet activation under high shear stress via multi-target suppression of PI3K/AKT and ERK1/2 pathways. A stenotic artery (left) represents the in vivo pathological condition of high shear stress, simulated using an in vitro microfluidic chip (right) with a constricted region. Whole blood is perfused through the chip, and platelet aggregation, activation, and blood compatibility are evaluated. Ginsenoside Rg1 suppresses the pro-thrombotic PI3K/AKT/ERK1/2 pathways while activating the inhibitory PKG/VASP pathway, leading to reduced platelet activation and aggregation (lower P-selectin expression and integrin αIIbβ3 activation). In conclusion, Ginsenoside Rg1 attenuates platelet activation under high shear stress via multi-target suppression of intracellular signaling, offering a promising strategy that warrants further in vivo validation.

The fundamental aspect of breast cancer metastasis is the infiltration of malignant cells, which can be blocked by propofol, a widely utilized anesthetic in clinical settings, as recent studies reporting. However, research utilizing three-dimensional invasion models in vitro has not been documented. This study created a microfluidic chip model utilizing type I collagen (Col1), integrating delayed dynamic imaging and several fluorescence labeling approaches to objectively assess the inhibitory effect of propofol on breast cancer cell MDA-MB-231 invasion. Research indicates that MDA-MB-231 cells demonstrate collective invasion behavior, with their invasive capacity reliant on the degradation of the extracellular matrix (ECM) facilitated by matrix metalloproteinases (MMPs): both the invasion distance and cell count diminish as matrix hardness (collagen concentration 1-2.5 mg/ml) increases, while they augment with extended culture duration (1-5 days). Subsequent research has demonstrated that propofol (12.5-50 μg/ml) can reduce both the invasion distance and quantity of MDA-MB-231 cells in a dose-dependent manner, potentially linked to the down-regulation of MMP-2/MMP-9 and the up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. This paper presents novel experimental evidence that propofol inhibits the invasion of breast cancer cells, and establishes a straightforward and quantitative medication evaluation platform, offering a methodological reference for the screening and mechanistic investigation of tumor microenvironment regulators.

Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors. However, no clinical data supporting this combination have been reported. Therefore, we conducted a clinical trial (NCT 04337463) to investigate the efficacy and safety of combining onatasertib, an mTORC1/2 inhibitor, with toripalimab, a PD-1 antibody in patients with advanced solid tumors. This open-label, phase 1/2 clinical trial included dose escalation and dose expansion cohorts to evaluate safety, tolerability, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). A total of 46 patients were enrolled and received onatasertib at doses of 15 mg, 20 mg, or 30 mg once daily (QD), combined with toripalimab 240 mg every 3 weeks (Q3W). No dose-limiting toxicities were observed, and the most common grade 3 or 4 treatment emergent adverse events were lymphopenia (23.9%) and rash (19.6%). The overall ORR was 26.1%, with a DCR of 73.9%, and a median PFS of 4.3 months. In cervical cancer patients, regardless of PD-L1 expression, the ORR was 52.4%, DCR was 90.5% and median PFS was 5.8 months. Notably, the 15 mg combination dose demonstrated a median PFS of 7.8 months. In conclusion, the safety profile of onatasertib in combination with toripalimab was manageable and showed encouraging clinical activity in advanced solid tumors, particularly among cervical cancer patients, irrespective of PD-L1 expression. The recommended phase 2 dose for the combination was determined to be onatasertib 15 mg QD and toripalimab 240 mg Q3W.

Cervical cancer constitutes a formidable health challenge imperiling the well-being and lives of women globally, particularly in underdeveloped nations. The survival rates among patients diagnosed with cervical cancer manifest considerable heterogeneity, shaped by a myriad of variables. Within the scope of this inquiry, a predictive model for projecting overall survival (OS) in cervical cancer patients was formulated and subsequently validated. Clinicopathological and follow-up information of patients diagnosed with cervical cancer were prospectively collected from May 1, 2015, to December 12, 2019, as part of an ongoing longitudinal cohort study conducted at Chongqing University Cancer Hospital. Subsequent to the acquisition of follow-up data, the sample was randomly divided into two cohorts: a training cohort (n = 2788) and a testing cohort (n = 1194). The predictors for the model were selected through least absolute shrinkage and selection operator (LASSO) regression analysis. Cox stepwise regression analysis was then employed to identify independent predictive indicators. The study results were subsequently presented in the form of static and web-based dynamic nomograms. To elucidate the objective validation of the prognosis and anticipated survival, the concordance index (C-index) was computed. The model’s discriminatory ability across various variables and its predictive performance were assessed through calibration plots. Additionally, the predictive model’s capacity for outcome prediction and its net benefit were evaluated using the Net Reclassification Index (NRI) and Decision Curve Analysis (DCA) curves. The final model regarded the following variables from the training cohort as independent risk factors for cervical cancer patients: age, medical insurance, pathology, HPV infection status, chemotherapy, β2-microglobulin, neutrophil-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR). The C-indices of OS for the training group were 0.769 (95

How to select muscle-invasive bladder cancer (MIBC) patients who are sensitive to immunotherapy is an unmet medical need. This study aimed to explore the role of immunoproteasome subunits as a novel signature for predicting efficacy of immunotherapy in MIBC. The expression profile of immunoproteasome subunits of MIBC and normal tissues was evaluated from data of The Cancer Genome Atlas (TCGA) and of the Chongqing University Cancer Hospital (CQUCH) cohort. Survival analysis and response to immunotherapy was further explored and compared between immunoproteasome subunitshigh and immunoproteasome subunitslow MIBC patients in the TCGA, the CQUCH and the IMvigor210 cohort. The association of the expression of immunoproteasome subunits with immune checkpoint molecules and the tumor immune microenvironment was explored by immunohistochemistry staining and bioinformatic analysis in MIBC of these three cohorts. The expression of the immunoproteasome subunits PSMB8, PSMB9 and PSMB10 was significantly upregulated in MIBC. MIBC patients with high expression of immunoproteasome subunits, especially high expression of PSMB9, showed a trend of prolonged overall and progression free survival, which was further significantly improved in response to immunotherapy. Bioinformatics and immunohistochemistry staining revealed a positive correlation of the expression of immunoproteasome subunits with the expression of immune checkpoint molecules, with T cell activation and with T cell-mediated cytotoxicity. Immunoproteasome subunits, in particular PSMB9, are immune microenvironment-related molecules of MIBC and are promising signatures for survival prediction in response to immunotherapy of MIBC.

In vitro assessment of the inhibitory effect of antiplatelet drugs on platelet aggregation is frequently employed to guide personalized antiplatelet therapy in clinical practice. However, existing methods for detecting platelet aggregation rely heavily on high concentrations of exogenous agonists, which may obscure part of the inhibitory effect of antiplatelet drugs and lead to an underestimation of their effects. This study validates a novel analytical strategy for evaluating the effects of antiplatelet drugs by quantifying the microscopic three-dimensional morphological parameters of platelet aggregates formed through spontaneous aggregation on a glass surface. Heparin-anticoagulated platelet-rich plasma (PRP) was applied to a glass surface to induce spontaneous platelet aggregation. The microscopic three-dimensional morphology of platelet aggregates was characterized using a laser three-dimensional microscopic imaging system, and platelet aggregation function was assessed based on the volume parameter (Vol) and cross-sectional area parameter (CS-area) of the aggregates. The results demonstrated that platelets could spontaneously aggregate on the glass surface under the participation of plasma proteins and Ca2+. Aspirin (80 μM) significantly reduced Vol but had no significant effect on CS-area. Ticagrelor, eptifibatide, and tirofiban dose-dependently decreased both Vol and CS-area. High concentrations of eptifibatide (4 μM) and tirofiban (4 μM) completely inhibited platelet adhesion and aggregation. The combination of aspirin (20 μM) and ticagrelor (0.5 μM) synergistically suppressed platelet aggregation behavior. GPIb-IX-von Willebrand factor (vWF) inhibitors (4 μM) and indomethacin (4 μM) significantly reduced both Vol and CS-area, with a smaller reduction in CS-area compared to Vol. In patients, aspirin alone significantly reduced Vol, while clopidogrel, aspirin combined with clopidogrel, and Xuesaitong significantly decreased both Vol and CS-area. Our novel analytical strategy is capable of distinguishing the pharmacological effects of various antiplatelet agents without the need for exogenous agonists, suggesting that this system may aid in the determination of the appropriate type and dose of the antiplatelet agent in the clinical setting. Antiplatelet drugs inhibit spontaneous aggregation of platelets on glass surface. The efficacy of antiplatelet drugs can be analyzed through the 3D morphological parameters of platelet aggregates. The novel strategy is capable of distinguishing the pharmacological effects of various antiplatelet agents without the need for exogenous agonists, suggesting that this system may aid in the determination of the appropriate type and dose of antiplatelet agent in the clinical setting.

OBJECTIVE:Cervical cancer (CCa) significantly affects female fertility and quality of life. This study aimed to construct and validate a random survival forest (RSF) model to identify the factors that affect the overall survival (OS) in patients with CCa in China and compare its performance with that of the Cox proportional hazards model (Cox model). METHODS:Data on CCa patients were collected from Chongqing University Cancer Hospital. The performance and discrimination ability of the models were evaluated via the C-index, integrated Brier score (IBS), accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). The Kaplan-Meier (K-M) survival curve was used to analyze the difference in OS between patients with high and low risk predicted by RSF model. RESULTS:A total of 3,982 patients were included in this study. Comparing to Cox model, the RSF model ranked important variables and identified radiotherapy (RT) as an important treatment measure. A comprehensive analysis of the evaluation indices confirmed that the RSF model outperformed the Cox model (IBS: 0.152 vs. 0.162, C-index: 0.863 vs. 0.764). The RSF model metrics for the validation cohort (VC) were as follows: 1-, 3-, and 5-year AUC (0.908, 0.884, and 0.869), sensitivity (0.746), specificity (0.825), and accuracy (0.808). The OS of low-risk patients predicted by RSF was greater than that of high-risk patients. CONCLUSION:The RSF model demonstrated excellent discrimination, calibrated predictions, and stratified risk for CCa patients. Furthermore, it outperformed the Cox model in predicting risks, thus enabling the delivery of personalised treatment and follow-up strategies.

e17500 Background: Targeted therapy for human epidermal growth factor receptor 2 (HER2) has become a standard of care in several HER2-expressing solid tumors. Nonetheless, there remains an unmet need for effective treatment, for instance, anti-HER2 antibody-drug conjugates (ADCs), in advanced stage gynecological cancer. In this context, we presented a retrospective study on the incidence of HER2 expression in primary gynecological cancer based on a single-center data from southwestern China. Methods: Paraffin-embedded tumor tissue blocks, clinicopathological, and survival data of gynecological cancer patients were collected from Chongqing University Cancer Hospital. HER2 IHC scoring was carried out according to the updated ASCO/CAP guidelines for breast and gastroesophageal adenocarcinoma by two pathologists independently. Data analysis was performed using SPSS v.24. Results: A total of 104 cases of cervical cancer, 102 cases of endometrial cancer and 103 cases of ovarian cancer were included between 2019 and 2023. HER2 expression was detected in 31.7% samples, with scores of 1+, 2+, and 3+ in 23.9% (74/309: 36/104, 16/102, 22/103), 5.8% (18/309: 7/104, 7/102, 4/103), and 1.9% (6/309: 2/104, 1/102, 3/103) of patients, respectively. Notably, ultra-low HER2 expression with incomplete and faint staining in ≤10% of tumor cells was observed in 41.1% (127/309: 37/104, 53/102, 37/103) of patients. Metastasis and lymphovascular invasion were associated with elevated HER2 expression in endometrial cancer (p=0.037, 0.040, respectively), while a larger tumor size was associated with elevated HER2 expression in cervical cancer (p=0.004). However, no positive association between HER2 status and overall survival (OS) was found in cervical, endometrial or ovarian cancer. In our cohort, metastasis was the only risk factor related to reduced OS of gynecological cancer patients by COX regression analysis (HR=14.00, 95%CI=1.32-148.21, p=0.028). Conclusions: Our data revealed a considerable number of patients with HER2-low and ultra-low gynecological cancer. It might represent a significant portion in real-world scenarios and warrant more consideration in selecting candidates for HER2-targeted ADCs, especially for those with relapsed or refractory conditions. Given the inherent challenge in interpretation, the study highlights the necessity for a consensus on evaluating HER2 immuno-staining results in gynecological cancer. Clinical trial information: MR-50-23-019676 . [Table: see text]

ABSTRACT:As the pathogenesis of arterial thrombosis often includes platelet adhesion and aggregation, antiplatelet agents are commonly used to prevent thromboembolic events. Here, a new microfluidic method without additional adhesion protein modification was developed to quantify the inhibitory effect of antiplatelet drugs on the adhesion and aggregation behavior of platelets on glass surfaces under physiological flow conditions. Polydimethylsiloxane-glass microfluidic chips were fabricated by soft photolithography. Blood samples from healthy volunteers or patients before and after taking antiplatelet drugs flowed through the microchannels at wall shear rates of 300 and 1500 second -1 , respectively. The time to reach 2.5% platelet aggregation surface coverage (Ti), surface coverage (A 150s ), and mean fluorescence intensity (F 150s ) were used as quantitative indicators. Aspirin (80 μM) prolonged Ti and reduced F 150s . Alprostadil, ticagrelor, eptifibatide, and tirofiban prolonged Ti and reduced A 150s and F 150s in a concentration-dependent manner, whereas high concentrations of alprostadil did not completely inhibit platelet aggregation. Aspirin combined with ticagrelor synergistically inhibited platelet adhesion and aggregation; GPIb-IX-von Willebrand factor inhibitors partially inhibited platelet aggregation, and the inhibition was more pronounced at 1500 than at 300 second -1 . Patient administration of aspirin or (and) clopidogrel inhibited platelet adhesion and aggregation on the glass surface under flow conditions. This technology is capable of distinguishing the pharmacological effects of various antiplatelet drugs on inhibition of platelet adhesion aggregation on glass surface under physiological flow conditions, which providing a new way to develop microfluidic platelet function detection method without additional adhesive protein modification for determining the inhibitory effects of antiplatelet drugs in the clinical setting.

Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood–brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH.

OBJECTIVE:Postoperative venous thromboembolism (VTE) is a potentially life-threatening complication. This study aimed to develop a predictive model to identify independent risk factors and estimate the likelihood of VTE in patients undergoing surgery for cervical cancer. METHODS:We conducted a retrospective cohort study involving 1,174 patients who underwent surgery for cervical carcinoma between 2019 and 2022. The cohort was randomly divided into training and validation sets at 7:3. Univariate and multivariate logistic regression analyses were used to determine the independent factors associated with VTE. The results of the multivariate logistic regression were used to construct a nomogram. The nomogram's performance was assessed via the concordance index (C-index) and calibration curve. Additionally, its clinical utility was assessed through decision curve analysis (DCA). RESULTS:The predictive nomogram model included factors such as age, pathology type, FIGO stage, history of chemotherapy, the neutrophil-lymphocyte ratio (NLR), fibrinogen degradation products (FDP), and D-dimer levels. The model demonstrated robust discriminative power, achieving a C-index of 0.854 (95% CI: 0.799-0.909) in the training cohort and 0.757 (95% CI: 0.657-0.857) in the validation cohort. Furthermore, the nomogram showed excellent calibration and clinical utility, as evidenced by the calibration curve and decision curve analysis (DCA) results. CONCLUSIONS:We developed a high-performance nomogram that accurately predicts the risk of VTE in cervical cancer patients undergoing surgery, providing valuable guidance for thromboprophylaxis decision-making.