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Hashimoto thyroiditis (HT) is closely associated with the development of papillary thyroid carcinoma (PTC); however, the tumor immune microenvironment and the molecular mechanisms underlying the 'inflammation-to-cancer' transition in HT-PTC coexistence remain poorly understood. In this study, we integrated single-cell RNA sequencing (scRNA-seq) data from HT-associated and PTC tissues, annotating 11 distinct cell subtypes, including endothelial cells, red blood cells, fibroblasts, follicular epithelial cells (FECs), macrophages, monocytes, T cells, NK cells, B cells, plasma cells, and mast cells. Malignant epithelial cells were identified through copy number variation (CNV) analysis, followed by differential gene expression screening and functional enrichment analysis. Cell-cell communication analysis was employed to delineate intercellular interactions, and key findings were validated using a lipopolysaccharide (LPS)-stimulated Transwell co-culture model incorporating TPC-1 cells, Nthy-ori 3-1 cells, and mast cells. We found that IL1B was significantly upregulated in malignant FECs, and differentially expressed genes were enriched in immune-related processes including antigen presentation and lymphocyte activation. Notably, IL1B^- FECs specifically communicated with mast cells via the FN1/CD44 signaling axis. In vitro experiments further confirmed that, under inflammatory conditions, mast cells secreted IL-8, which activated the PI3K/AKT pathway and promoted malignant phenotypes. Collectively, these findings suggest that IL1B⁻ FECs recruit mast cells through the FN1/CD44 axis, and mast cell-derived IL-8 subsequently activates the PI3K/AKT pathway to drive the transformation from HT to PTC, providing novel mechanistic insights into the "inflammation-to-cancer" transition.

Background: The endometriosis painful symptoms-4 dimensions ENDOPAIN-4D is a multidimensional questionnaire designed to assess endometriosis-related pain. This study aimed to translate, culturally adapt, and validate ENDOPAIN-4D for European Portuguese.

Methodology: Translation and content validity assessment were assessed in 32 women with endometriosis. For psychometric validation, 386 patients completed an online sociodemographic and clinical questionnaire, the Portuguese ENDOPAIN-4D, and the Endometriosis Health Profile Questionnaire-30 (EHP-30). Statistical analyses included descriptive statistics, exploratory factor analysis, internal consistency, item-total correlation, and concurrent validity.

Results: Factor analysis of the "usual pain" dimension supported the original four-factor structure, accounting for 63.7% of variance (Cronbach's α = 0.91). A novel three-factor structure was identified for the "worst pain" dimension, previously psychometrically untested, with good internal consistency (Cronbach's α = 0.83) and acceptable item-total correlations. Concurrent validity with the EHP-30 ranged from weak to strong across domains.

Conclusions: The Portuguese ENDOPAIN-4D is a culturally adapted and validated instrument for multidimensional pain assessment in European Portuguese women with endometriosis, with validity likely limited for other Portuguese-speaking communities. The newly identified three-factor structure for worst pain may aid individualized pain management and follow-up in clinical and psychosomatic care. Further studies should evaluate concurrent validity and the stability and responsiveness of the new algorithms.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, yet their efficacy is limited by high-grade immune-related adverse events that often require treatment with systemic corticosteroids. Although corticosteroids are widely used, their impact on anti-tumor immunity remains poorly defined. Using an ICI-responsive murine melanoma model, we show that tapered systemic prednisolone administered after three cycles of combined anti-CTLA4 and anti-PD1 therapy compromises ICI-mediated tumor control, leading to delayed progression in one-third of initially responding animals. Mechanistically, prednisolone selectively suppressed CD8⁺ effector T-cell activation in tumor-draining lymph nodes and in the circulation, while expanding activated regulatory T-cells. These changes increased the Treg:CD8⁺ effector ratio, reduced cytotoxic T-cell function and blocked the early ICI-mediated induction of cytokines, including IL-2, IFNγ, VEGF, CCL3/4, IL-13, IL-3, and GM-CSF. Importantly, despite these early immunosuppressive effects, long-term tumor-specific memory responses were preserved. Autologous melanoma:T-cell cocultures validated these findings. Overall, systemic prednisolone disrupts early CD8⁺ T-cell-mediated anti-tumor activity but spares durable immunity, highlighting the critical importance of timing and context in the introduction of corticosteroids during ICI therapy.

Estimates of the added benefit from COVID-19 vaccine booster doses can inform seasonal vaccine recommendations. We set out to estimate COVID-19 vaccine effectiveness (VE), avoiding common sources of bias. We chose a modified screening method, using only vaccinated cases of symptomatic COVID-19 recorded in the mandatory infectious disease reporting system, with data from a vaccination registry. Effect estimates were obtained by Bayesian logistic regression, comparing outcomes within dose strata between immunized (15-21d after vaccination) and not yet immunized (up to 7d). VE estimates were calculated recursively and relative VE estimates were obtained to quantify the added benefit of booster doses. We found VE for clinical illness to be around 90% during the predominance of the SARS-CoV-2 Alpha variant. During the Delta period, VE was distinctly lower, but did not decrease much further. The first booster dose added substantial protection during the Delta period, but that benefit became marginal during the Omicron period in the 18+. The effect of second booster doses, which became widespread only during the Omicron period, was modest. Using a novel, vaccinated-only study design we found that two doses of a COVID-19 vaccine offered substantial protection from symptomatic COVID-19, even during the Omicron period. One booster dose was highly effective during the Delta period, but the effect became modest during the Omicron period, when second booster doses offered, but a marginal benefit.

Cisplatin-based concurrent chemoradiation (CRT) remains the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), yet recurrence rates remain high. Attempts to combine immune checkpoint inhibitors with CRT have not improved outcomes, underscoring the need to better understand CRT-driven immunologic dynamics. Here, we performed longitudinal, multidimensional profiling of peripheral immunity in patients with LA-HNSCC at baseline (BSL), one month (CRT-1M), and three months (CRT-3M) after platinum-based CRT. CRT induced a transient reduction in tumor-reactive Th1 responses at CRT-1M, followed by marked expansion by CRT-3M. Consistently, genes involved in T-cell activation, polarization, and exhaustion exhibited a biphasic pattern with delayed upregulation at CRT-3M. Transcriptomic analyses of blood lymphocytes revealed an early shift from B-cell- to T-cell-mediated pathways over time during CRT. Integrated analyses including immunosuppressive cells and soluble mediators showed that the early decline in tumor-reactive T cells coincided with increased immunosuppressive cells, T-cell exhaustion, and elevated protumoral cytokines such as IL-8, IL-1β, and IL-10. In contrast, robust expansion of tumor-reactive T cells dominated the peripheral immune landscape at CRT-3M. Together, these data reveal the dynamic remodeling of peripheral immunity following platinum-based CRT and identify a delayed peripheral immune activation phase that may represent an optimal window for combining CRT with immune checkpoint blockade.

Aluminum (Al³⁺) toxicity is a major limitation to plant productivity in acidic soils, disrupting cellular homeostasis, redox balance, and nutrient uptake. Brassinosteroids are key regulators of plant stress signaling, yet their role in Al³⁺ tolerance remains insufficiently understood. Here, we investigated the signaling functions of 24-epibrassinolide (24-EBL) in mediating aluminum stress responses in Nicotiana tabacum grown under soilless culture conditions. Exogenous 24-EBL significantly alleviated Al³⁺-induced photosynthetic inhibition, as reflected by increased transpiration rate (Tr), stomatal conductance (Gs), net photosynthetic rate (Pn), electron transport rate (ETR), and effective quantum yield of PSII (ΦPSII). Enhanced non-photochemical quenching (NPQ) indicated improved dissipation of excess excitation energy, suggesting photoprotective regulation. At the molecular level, 24-EBL treatment upregulated the antioxidant defense genes CAT1, NtPOD1, and NtSOD3, leading to increased enzymatic activities and reduced reactive oxygen species (ROS) accumulation, thereby preserving membrane stability. Notably, 24-EBL modulated metal detoxification pathways by inducing the expression of the phytochelatin-related genes Pr8 and Pr2, along with Al-ATPase transporters associated with vacuolar sequestration. This was accompanied by altered ion homeostasis, where enhanced Ca²⁺ and K⁺ uptake antagonized Al³⁺ accumulation and restricted its translocation to shoots. The marked upregulation of calmodulin (CaM) suggests that Ca²⁺-dependent signaling plays a central role in 24-EBL-mediated aluminum tolerance. Correlation analysis revealed strong associations between CaM expression, photosynthetic efficiency, antioxidant capacity, and metal detoxification markers. Together, these findings indicate that 24-EBL enhances aluminum tolerance in tobacco through a coordinated signaling network involving Ca²⁺-mediated signal transduction, redox regulation, and metal homeostasis. This study highlights brassinosteroid-calcium crosstalk as a key regulatory module in plant adaptation to aluminum stress.

Vaccination remains one of the most cost-effective methods for disease prevention. However, utilization of self-paid vaccines, including EV71, varicella, influenza, and DTaP-IPV-Hib in this study, remains insufficient among children under six in China. To investigate the determinants of willingness to vaccinate (WTV) for self-paid vaccines and assess cost-WTV heterogeneity, we conducted structured-questionnaire surveys with 2212 randomly selected households in Hangzhou, each with at least one child under six. Multiple regression analysis was used to identify the key determinants of WTV, and a mixed-effect model was employed to analyze the correlation between vaccine cost and WTV, further segmenting the data with unsupervised clustering techniques. Our findings highlighted impact of vaccination cost as a pivotal factor influencing the WTV for self-paid vaccines. We categorized the population into four groups based on their sensitivity to vaccine cost. Families with one child, children aged 1-3 y, highly-educated parents, and higher socioeconomic status consistently exhibited high WTV. Our analysis offers targeted strategies to enhance vaccine uptake and improve immunization coverage.

Purpose: Cystic fibrosis (CF) is a genetic disease primarily affecting the lungs and digestive system. Individuals with advanced CF lung disease may require transplantation to survive. Family members often take on significant caregiving roles, facing both emotional and practical challenges throughout the transplantation process. This study explores the experiences of such family members to inform and improve supportive care practices.

Method: Employing a naturalistic, exploratory design, this qualitative study used purposive sampling to recruit 19 family members of lung transplant recipients with CF. Data were collected through semi-structured interviews and analysed using reflexive thematic analysis.

Results: The analysis identified three main themes and eight subthemes: (I) balancing hope and despair on the waiting list, (II) navigating challenges and finding relief after the transplantation, and (III) unmet support and informational needs before and after transplantation.

Conclusion: This study highlights the emotional burden and caregiving responsibilities shouldered by family members of individuals with CF who have undergone lung transplantation. The findings emphasise the importance of person- and family-centred interventions, including support for palliative care discussions. A more structured and inclusive framework is essential to address the often-overlooked needs of families throughout the transplantation process.

Objective: Clear-cell renal cell carcinoma (ccRCC) is an immune-desert tumor. This study investigates the role of ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) as a potential therapeutic target and immune-checkpoint enzyme in ccRCC.

Methods: ENPP3 expression and its link to hypoxia and prognosis were analyzed in ccRCC. Functional roles were tested using gain/loss-of-function studies in vitro and in xenograft models, followed by therapeutic anti-ENPP3 antibody administration, alone or with anti-PD-L1. Mechanisms were explored via promoter analysis, cGAMP measurement, flow cytometry, cytokine profiling, and in vivo neutralization with STING- or interferon-α/β receptor-1 (IFNAR1) blocking antibodies.

Results: ENPP3 is hypoxia-inducible via HIF-1α, upregulated in ccRCC, and predicts poor prognosis. ENPP3 overexpression accelerated tumor growth, while its knockdown or antibody blockade inhibited progression and synergized with anti-PD-L1. Mechanistically, ENPP3 hydrolyzes extracellular cGAMP. Its depletion elevated extracellular cGAMP, expanded anti-tumor immune cells (M1 macrophages, cDC1s, and cytotoxic T cells), reduced Tregs, and induced a STING- and IFNAR1-dependent type I interferon signature in macrophages. The anti-tumor efficacy of ENPP3 blockade was abrogated by IFNAR1 inhibition.

Conclusion: ENPP3 is a hypoxia-driven, cGAMP-targeting innate immune checkpoint in ccRCC. Its inhibition reactivates STING-dependent anti-tumor immunity, providing a strong preclinical rationale for targeting ENPP3 therapeutically.

Salicylic acid (SA) is a key signaling molecule that regulates various physiological and biochemical processes in plants. This study evaluated the role of foliar-applied SA in alleviating arsenic (As) toxicity and improving the growth and anatomical traits of three wheat cultivars (Anaaj-17, Dilkash-20, and Subhani-21) under As stress. Exposure to As (300 and 500 µM) significantly reduced plant height, leaf length, fresh and dry biomass, photosynthetic pigments (chlorophyll a and b), relative water content, and disrupted leaf and root anatomical structures, including the lower and upper epidermis, cortex, xylem, and phloem thickness. Foliar application of SA (0.5 and 1 mM) mitigated these adverse effects, enhancing growth, chlorophyll content, and vascular and epidermal development in all cultivars. These findings highlight the protective role of SA against As-induced stress, suggesting that its application can improve crop resilience, physiological performance, and anatomical integrity in contaminated soils. The incorporation of SA into crop management practices could contribute to enhanced productivity and sustainable agricultural returns in arsenic-affected areas.