全部最新文献

NF-YA1 (nuclear factor Y, subunit A1) is a key transcription factor that participates in the regulation of plant growth and stress responses. In plants, NF-YA proteins are encoded by multigene families and play crucial roles in controlling gene expression related to development, metabolism, and adaptation to environmental constraints. Therefore, NF-YA transcription factors are considered promising targets for improving plant tolerance to abiotic stress. In our previous study, we demonstrated that TdNF-YA2A-1 transcripts from durum wheat are induced by various abiotic stressors, and that heterologous expression of this gene enhances stress tolerance in yeast. Herein, we functionally investigated its role in transgenic tobacco. RT-qPCR analysis demonstrated that TdNF-YA2A-1 expression was differentially regulated in durum wheat tissues subjected to salt (150  mM NaCl), osmotic (10% PEG 8000), and oxidative (10 µM H₂O₂) stresses. Transgenic TdNFY-YA2A-1-overexpressing tobacco lines exhibited enhanced tolerance to both salt and osmotic stress relative with non-transgenic (NT) plants. This enhanced tolerance was correlated with a reduction in oxidative damage and the upregulation of several stress-responsive genes involved in antioxidant defense and stress signaling. Taken together, our results suggest that TdNF-YA2A-1 is a promising candidate gene for developing crops with improved tolerance to salt and osmotic stresses.

Background: Gliomas, including glioblastomas (GB) and high-grade astrocytomas (HGA), are the most common brain tumors in adults, with poor survival rates around 15 months. Hormonal factors, particularly progesterone receptor (PR) activation, promote tumor growth. Current treatment involves surgery, radiotherapy and chemotherapy (temozolomide), but survival rates remain low. Repurposing mifepristone (MF), a contraceptive drug, shows promise for GB treatment, warranting further study.

Methods: PR expression in U87, U251 and C6 cell lines were assessed using immunofluorescence and Western Blot. PR isoforms were quantified by densitometry. Progesterone (P4) and 5α-dihydroprogesterone (5α-DHP) synthesis were evaluated using LC/MS. MF's effect on cell viability was determined by IC₅₀ and IC₂₀ values. Its impact on non-tumoral cells and 3D glioma sphere formation was also analyzed. The effects of in situ administration of MF were assessed in vivo using a rat model with C6 glioma implants. Clinical outcomes were evaluated in GB patients receiving MF alongside standard treatment.

Results: PR was predominantly nuclear in all cell lines, with U87 showing the highest PR-B isoform levels. Only U251 synthesized 5α-DHP significantly. MF reduced viability in U251, U87 and C6 cells without affecting non-tumoral cells. Sphere formation efficiency decreased with MF treatment. In rats, MF reduced tumor volume dose-dependently. Clinically, MF improved patient survival from 165 to 588days and enhanced quality of life without severe adverse effects.

Conclusion: MF effectively reduces GB cell viability, sphere formation efficacy and tumor volume. These findings support further investigation of MF as a therapeutic strategy in GB treatment.

Précis (condensed abstract): Our research highlights the critical role PR in GB progression using in vitro and in vivo models. MF, a PR modulator, effectively reduced cell viability and sphere formation in cellular assays and significantly decreased tumor volume in an in vivo study. The pilot trial demonstrated the pharmacological safety of using MF as an adjuvant in GB treatment. Patients treated with MF showed a significant increase in survival, with an 80% survival rate at 1 year compared to 0% in those who were treated with the standard treatment.

Background: The potential of Lenvatinib to synergize with combined radiotherapy and immunotherapy in LUAD remains incompletely characterized.

Methods: We investigated Lenvatinib's effects on radiation-induced PD-L1 in LUAD cells and VEGFR2 in HUVECs via Western blot, VEGFA expression via RT-qPCR/ELISA, and angiogenesis via immunofluorescence. LUAD-HUVEC crosstalk was modeled in vitro. In C57BL/6 mice bearing LUAD tumors, we evaluated the efficacy of RT and anti-PD-L1 with or without Lenvatinib, monitoring tumor growth, survival, and profiling the tumor microenvironment by mIHC and flow cytometry.

Results: Lenvatinib suppressed radiation-induced PD-L1 and VEGFR2 expression, inhibited angiogenesis, and disrupted HUVEC-facilitated LUAD proliferation. The triple-combination (RT + anti-PD-L1 + Lenvatinib) significantly suppressed tumor progression (P < 0.05) and extended median survival (34 vs. 29.5 days, P < 0.05) versus dual therapy. It also enhanced intratumoral CD8⁺ T-cell infiltration and cytotoxicity, promoted M1-like macrophage polarization, and reduced regulatory T cell frequency and microvessel density.

Conclusions: Lenvatinib potentiates RT and anti-PD-L1 therapy in LUAD through dual immune-vascular modulation, supporting the clinical translation of this triple-combination strategy.

Receptor-mediated transcytosis (RMT) represents a promising strategy for delivering macromolecular and colloidal therapeutics across the blood-brain barrier (BBB). However, mechanistic elucidation of RMT remains limited by the difficulty of visualizing subcellular trafficking pathways. Conventional imaging approaches either lack sufficient spatial resolution or require costly, technically complex instrumentation. Here, we report a cell swelling and upright mounting-based (CSUM-based) imaging approach that reorients the Z-axis into the high-resolution XY-plane using standard confocal microscopy, enabling direct RMT visualization without computational reconstruction or specialized hardware. We tracked intracellular trafficking of transferrin (Tf) and anti-transferrin receptor antibody (anti-TfR Ab) as model cargos using our CSUM-based imaging approach via compartment-specific markers and time-resolved co-localization analysis. This approach resolved cargo-containing vesicles traversing from the apical to basolateral membranes. Tf completed transcytosis within 15 min, whereas anti-TfR Ab initially entered the endolysosomal pathway before rerouting to transcytosis under receptor saturation conditions. The CSUM approach provides a simple yet effective platform for high-resolution visualization of membrane transport and vesicle dynamics, offering broad applicability to drug delivery research and the design of brain-targeted therapeutics.

Combining radiotherapy with immune checkpoint inhibitors (RT-ICI) triggers systemic antitumor responses, such as abscopal effects (AbE). Predictors of AbE and its impact on survival in real-world settings remain poorly defined. This multicenter, retrospective cohort study assessed the prevalence of AbE in ICI-refractory progressive metastatic patients by evaluating the additive effect of RT on nonirradiated lesions (NIL). We screened 3773 cases to identify patients with stage IV tumors receiving RT during/after ICI. Abscopal benefit (AB) was defined as abscopal response (AR) or control (AC) by measuring NILs according to iRECIST. AB was observed in 61.3% of 142 included patients and associated with improved median overall survival (18 vs. 8 months, p < 0.01) and progression-free survival (7 vs. 3 months, p < 0.01). Logistic regression identified younger age (OR = 0.951, 95% CI: 0.903-0.995, p = 0.039) and longer ICI-RT intervals (OR = 1.077, 95% CI: 1.019-1.171, p = 0.027) as predictors of AB. There was no association between radiation dose or tumor volume and AB. Cox regression identified BMI ≥ 25 kg/m² (HR = 3.348, 95% CI: 1.557-7.202, p = 0.002) and CRP ≥ 5 mg/l (HR = 3.058, 95% CI: 1.211-7.724, p = 0.016) as independent negative prognostic factors for survival in this RT-ICI cohort. Median survival was significantly higher among patients receiving ultrahypofractionated RT, compared to other fractions (21 vs. 11 months; p = 0.024). AbE seems to occur reliably and is prognostically relevant in ICI-refractory patients receiving RT. Patient- and timing-related factors were more predictive than RT details in our cohort. Our findings enhance the understanding of tailored RT-ICI approaches and lay the groundwork for targeted radioimmunotherapy strategies and personalized clinical trial designs.

Background: Circulating microRNA-210-3p (miR-210-3p) is a hypoxia-related regulator implicated in placental maladaptation. Its longitudinal behavior across hypertensive disorders of pregnancy (HDP), and whether low-dose aspirin modifies its trajectory, remain insufficiently understood.

Methods: This prospective case-control study was conducted between October 2021 and November 2024. Circulating miR-210-3p was measured in the first trimester and at delivery. Aspirin use followed routine clinical practice for preeclampsia prevention. Longitudinal trajectories were examined using generalized estimating equations (GEE) as the primary analytic approach and linear mixed effects models (LMM) as a secondary method.

Results: Ninety-four women were enrolled, including 73 controls, 11 with gestational hypertension, and 10 with preeclampsia. miR-210-3p increased significantly from the first trimester to delivery in gestational hypertension (p = 0.003) and preeclampsia (p = 0.006), with no significant change in controls. In the first trimester, gestational hypertension exceeded controls (p = 0.006), and preeclampsia exceeded both groups (both p < 0.001). At delivery, gestational hypertension and preeclampsia remained higher than controls (both p < 0.001), and preeclampsia exceeded gestational hypertension (p = 0.036). GEE demonstrated a significantly slower rise in miR-210-3p among aspirin users with gestational hypertension (p = 0.042), and this association strengthened in sensitivity analysis (p = 0.001). LMM showed a similar, non-significant trend.

Conclusion: miR-210-3p exhibited disorder-specific longitudinal patterns across HDP. Aspirin-associated changes were observed in gestational hypertension but not in preeclampsia, suggesting differences in molecular expression trajectories between the two conditions over the course of gestation, while the underlying biological mechanisms remain to be clarified.

Gamification is increasingly adopted in health professions education to enhance clinical reasoning, a core competency essential for safe patient care. Although many interventions report positive outcomes, the magnitude and consistency of these effects remain uncertain. This meta-analytic review synthesizes quantitative findings on the effectiveness of gamified learning on clinical reasoning in medical and allied health learners across diverse contexts. Following PRISMA 2020 guidelines, we searched MEDLINE, Scopus, and Web of Science (2010-2023) for randomized and non-randomized studies evaluating gamified interventions targeting clinical reasoning. Eligible populations included pre- and post-licensure learners, with traditional or non-gamified instruction as comparators. Quantitative measures of clinical reasoning were required. Risk of bias was assessed using RoB 2.0 and ROBINS-I, and standardized mean differences (SMDs) were pooled using a random-effects model. From 713 records, 26 studies met inclusion criteria and 10 contributed to the meta-analysis. Gamified interventions were associated with improved clinical reasoning compared with traditional instruction (SMD = 1.11; 95% CI: 0.69-1.52). Substantial heterogeneity was observed (I² = 85%). Assessment of publication bias suggested possible overestimation of effects, with an adjusted pooled estimate of 0.75 (95% CI: 0.24-1.27). The certainty of evidence was rated as low due to heterogeneity, risk of bias, and potential publication bias. Gamified learning may support the development of clinical reasoning in health professions education; however, considerable variability across studies and low certainty of evidence warrant cautious interpretation. Future research should employ theory-informed designs, validated reasoning measures, and rigorous methodologies to clarify when and how gamification is most effective.

A concerning trend has recently emerged in Libya where cancer patients are seeking unproven herbal remedies derived from local Artemisia species driven by circulating claims on social media. These unregulated traditional medicines can interact with standard cancer treatments such as chemotherapy and radiation therapy. Scientific evidence suggests that Artemisia compounds can alter drug metabolism through enzymatic pathways (notably the CYP450 system), potentially neutralizing treatment efficacy or exacerbating systemic toxicity. This letter evaluates the toxicological profile of Artemisia and proposes an ethical framework for patient protection and public health intervention in Libya.

Liver X receptor β (LXRβ) is a key transcription factor involved in lipid metabolism and immune regulation, yet its functional role in tumor-infiltrating T cells remains largely unresolved. While LXRβ has been shown to suppress NF-κB target gene expression, the mechanistic interaction between LXRβ and NF-κB signaling in the tumor microenvironment (TME) has not been fully established. In this study, we identify LXRβ as a critical regulator of CAR-T cell differentiation, the metabolic state, and effector function within solid tumors. LXRβ overexpression altered the transcriptional and phenotypic landscape of CAR-T cells, including the modulation of stem-like TCF1⁺ populations, proliferative capacity (Ki-67), and cytokine production (IFNγ, TNFα). Through genetic perturbation of NF-κB components, particularly RelB, we further demonstrate that disrupting non-canonical NF-κB signaling enhances CAR-T cell cytotoxicity and attenuates exhaustion-related features such as TOX upregulation. Notably, combined targeting of LXRβ and RelB produced additive and, in some settings, synergistic benefits, improving metabolic fitness, reducing terminal exhaustion, and augmenting anti-tumor activity in vivo. Together, these findings define an LXRβ-NF-κB regulatory axis that shapes CAR-T cell fate and function in the TME and highlight this pathway as a promising target for improving CAR-T cell-based therapies against solid tumors.

By 2050, more than 61 million people worldwide are expected to lose their vision due to conditions like age-related macular degeneration, glaucoma, diabetic retinopathy, and uveitis (Bourne et al. 2021). This anticipated rise highlights the urgent need for more effective treatment options. While progress continues in developing new pharmacological agents, treating ocular diseases with these therapies remains particularly challenging due to the eye's unique and complex anatomy. This is largely due to the limitations of current drug delivery methods, including systemic administration, topical delivery application, transscleral/periocular drug delivery, and intravitreal injections, which are associated with low bioavailability, side effects, and rapid drug clearance. Given these challenges, microneedles have emerged as a promising alternative. Their minimally invasive nature and ability to precisely target the anterior and posterior segments make them well suited for enhancing therapeutic outcomes while reducing systemic exposure and potential side effects, as well as improving patient adherence (Kang-Mieler et al. 2017; Gadziński et al. 2022). The purpose of this review is to discuss recent advancements, key challenges, and strategies for microneedle-based ocular drug delivery systems, with an emphasis on their potential to treat both anterior and posterior eye diseases.