Search Results (656)

Background/Objectives: Breast cancer is a heterogeneous and complex disease with significant individual differences in molecular immunophenotype, biological behavior, histopathological morphology, and response to chemotherapy. The presence of tumor-infiltrating lymphocytes (TILs) has gained considerable attention due to growing evidence of their involvement in therapeutic efficacy, particularly in the response to neoadjuvant chemotherapy (NACT). Different immune cell subsets’ frequency, location, and functional orientation vary substantially between tumor types and individuals with apparently identical cancers. Currently, next-generation sequencing (NGS) has provided key insights into the composition of the tumor microenvironment. Simultaneously, immunohistochemistry (IHC) of paraffin-embedded biopsies allows the visualization of marker proteins within the immune infiltrate, thereby enhancing our understanding of the role of immune cells in cancer therapy. Methods: This exploratory study evaluated immune cell tumor infiltration using NGS with immune cell deconvolution, as well as automated IHC on Tru-Cut biopsies from 57 patients with locally advanced breast cancer. Image analysis was performed using Qupath v0.6.0 software. The percentage of infiltrating CD4+ or CD8+ T cells was determined, along with the expression of the markers FoxP3, LAG3, CTLA4, PD1, and TIM-3. We aimed to gain insights into the tumor microenvironment and its influence on the response to NACT in patients with breast cancer. Results: Transcriptomic immune deconvolution approaches suggested that a biased cytotoxic tumor environment is linked to chemosensitivity. IHC assays of individual markers reveal that baseline immune cell abundance and individual checkpoint expression did not differ significantly across the response groups. However, the functional organization and coordination of the tumor immune microenvironment showed distinct associations with chemosensitivity. Conclusions: Features representing immune balance, such as CD8/CD4 ratio and T cell-contextualized metrics, emerged as candidate predictors of pathological response to NACT, outperforming molecular phenotype alone in this exploratory cohort. Full article

Background: Endometriosis is a complex condition that impairs women’s quality of life and reproductive potential. Its diagnosis remains significant challenge for clinicians. The aim of the study was to investigate cancer-like immune evasion mechanisms in endometriosis and to develop a novel diagnostic model using machine learning. Methods: In this study, we measured the levels of soluble forms of the following immune markers in blood serum and peritoneal fluid (PF): sMICA, sMICB, sEng, sCD25, s4-1BB, sB7.2, sCTLA-4, sPD-L1, sPD-1, sTIM-3, sLAG-3, and sGal-9. Results: sMICB levels in PF differed across endometriosis stages and were higher in patients with endometriosis-associated adhesions. sMICA levels in PF were elevated in women with endometriosis-associated infertility. The disease severity was inversely correlated with serum sB7.2 levels and positively correlated with serum sTIM-3 levels. A logistic regression model achieved an accuracy = 0.79, AUC = 0.94, and F1-score = 0.88, whereas XGBoost performed better with accuracy = 0.94, AUC = 0.95, and F1-score = 0.96. The key predictive features in both models were sMICB serum level and patients’ pain score. Conclusions: Our results demonstrate the potential role of sMICA and sMICB shedding in endometriosis and present a novel, minimally invasive diagnostic approach. Full article

Gliomas exhibit considerable molecular heterogeneity and immunological complexity, emphasizing the need for effective biomarkers and therapeutic targets. In this study, the Chinese Glioma Genome Atlas (CGGA-325/693) and The Cancer Genome Atlas (TCGA-LGG/GBM) cohorts were used to explore the pathological role of PHD finger protein 23 (PHF23) in gliomas. Machine learning algorithms were performed to construct a PHF23-related prognosis signature (PHF23-RPS). Our analysis revealed significant upregulation of PHF23 in high-grade gliomas, while the PHF23-RPS exhibited strong predictive performance (AUC = 0.853). Two molecular subtypes were identified; Cluster 2 was characterized as “inflamed yet immunosuppressive”. This subtype displayed a tumor mutational burden (TMB) paradox, where elevated TMB failed to translate into survival benefits due to extensive M2 macrophage infiltration and checkpoint-mediated immune exhaustion. Pharmacogenomic screening and molecular dynamics simulations identified Entospletinib as a potential candidate targeting this immunosuppressive barrier, showing a stable binding affinity (−7.7 kcal/mol). Functional assays, including in vitro experiments and in vivo experiments via a male BALB/c nude mouse orthotopic glioma model (n = 6/group), confirmed that PHF23 silencing inhibited glioma malignancy. Our results identify PHF23 as a critical oncogenic driver in glioma and support the PHF23-RPS for risk stratification. Entospletinib may offer a potential immunomodulatory option for high-risk gliomas. Full article

Tumor-infiltrating lymphocytes (TILs) are an established predictor of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in breast cancer. However, TILs primarily reflect the extent of immune infiltration and provide limited insight into immune functional state. We investigated whether integrating measures of immune infiltration (TILs), effector T-cell presence (CD8), and functional context (immune checkpoint components) may improve prediction of pCR beyond TILs alone. Pretreatment tumor biopsies from 166 patients with early breast cancer treated with standard NACT were assessed for stromal TILs and mRNA expression of CD8, PD-1, LAG-3, and TIM-3. Associations with pCR were evaluated using univariate and multivariable logistic regression, and composite immune phenotypes were constructed to capture functional immune states. In univariate analyses, higher TILs, CD8, PD-1, and LAG-3 were associated with pCR (all p < 0.05), whereas TIM-3 was not (p = 0.801). In multivariable models, TILs remained independently associated with pCR when adjusted for checkpoint markers, but this association was attenuated when CD8 was included, consistent with the strong biological correlation between TILs and CD8, and neither CD8 nor checkpoint markers retained independent significance. PD-1 and LAG-3 expression strongly correlated with CD8 and moderately correlated with TILs, indicating that checkpoint expression predominantly reflects an immune effector–engaged tumor microenvironment. Composite immune phenotypes based on CD8/PD-1 co-expression identified distinct immune functional states, with CD8-high/PD-1-high tumors demonstrating the highest pCR rates. Hierarchical modeling showed modest improvements in discrimination with sequential addition of immune variables to clinical predictors, with the integrative CD8/PD-1 model achieving the highest discrimination within the cohort (AUC = 0.849), although the magnitude of improvement beyond TIL assessment alone was limited. In conclusion, immune infiltration, effector T-cell presence, and functional immune context represent complementary dimensions for pCR prediction following NACT in breast cancer. However, TILs remain the most robust and clinically feasible immune biomarker. Full article

This study presents a systematic review of Explainable Artificial Intelligence (XAI) applications in Transportation Infrastructure Management (TIM), focusing on predictive maintenance of safety-critical assets such as railways and bridges. A predefined review protocol was implemented, and peer-reviewed literature was systematically retrieved from Web of Science and Scopus covering the period 2015 to March 2025. Using structured Boolean search logic and clearly defined inclusion and exclusion criteria—requiring explicit integration of explainability within AI-driven infrastructure maintenance—450 records were initially identified, screened in multiple stages, and refined to 163 eligible studies for detailed analysis. Through structured data extraction and thematic synthesis, the review develops a taxonomy of model-specific, model-agnostic, hybrid, and human-centered XAI approaches while identifying recurring challenges including heterogeneous multi-modal data environments, lack of standardized interpretability metrics, computational constraints in real-time deployment, limited robustness validation under field conditions, and unresolved performance–interpretability trade-offs. The findings demonstrate systematic growth in XAI-driven predictive maintenance research and highlight the need for domain-specific benchmarks, hybrid interpretable architectures, digital twin-assisted validation, and edge-enabled explainable systems to enable scalable, transparent, and regulation-ready infrastructure management aligned with Industry 5.0. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide and is frequently diagnosed at advanced stages, when metastatic dissemination is already present. Tumour hybrid cells (THCs) are rare circulating cells formed through fusion between cancer stem cells with leukocytes, predominantly monocytes. These cells combine traits from both lineages, conferring enhanced migratory, invasive and immune-evasive capacities that could promote metastasis. In parallel, soluble immune checkpoints (sICs) have emerged as minimally invasive biomarkers and indicators of systemic immune dysregulation and tumour-driven immune escape. In this study, 31 patients with lung cancer were prospectively enrolled at La Paz University Hospital (Madrid, Spain). Circulating THCs were quantified by spectral flow cytometry, and plasma sICs concentrations were determined using multiplex immunoassays. Patients were stratified by metastatic status and survival. Variables showing the strongest discriminative capacity were integrated into multivariable logistic regression models. Number of THCs, and levels of sCTLA-4, s-41BB, sLAG-3, and sTIM-3 exhibited the strongest discrimination for metastasis, while THCs, sLAG-3, and sTIM-3 distinguished deceased from surviving patients. Integrating predictive models demonstrated high accuracy, and survival analyses supported their prognostic significance. These findings indicate circulating THCs and selected sICs represent promising liquid biomarkers for monitoring lung cancer progression and patient outcomes. Full article

Thermal interface materials are critical components for ensuring efficient heat dissipation in thermal management systems. The current research focus is to fabricate thermal interface materials (TIMs) that demonstrate high thermal conductivity while at low filler loadings. In this study, an aligned, thermally conductive skeleton was fabricated via the freeze casting method, utilizing carbon nanofibers (CNFs) and nickel (Ni) particles. This skeleton was subsequently infiltrated with silicone rubber (SR) to obtain the polymer composite. Within the aligned skeleton, CNFs and Ni particles are densely packed, with the Ni particles acting as conductive bridges between adjacent CNFs. This bridging effect facilitates a substantial enhancement in the overall thermal conductivity with only a minimal addition of Ni. By combining the skeleton’s microstructure with thermal performance, the effects of key parameters on thermal conductivity were systematically investigated. A maximum thermal conductivity improvement of 64.8% was achieved by hybridizing CNFs with a small amount of Ni (1.09 vol%) compared to the CNF-only counterpart. Furthermore, at a low total loading (8.02 vol% CNFs and 1.09 vol% Ni), the composite achieved a thermal conductivity of 3.30 W/(m·K). This value was 47.2% higher than that of a CNF-only TIM and 36.2% higher than that of a composite prepared by common freezing under the same filler composition. Additionally, the incorporation of Ni enhanced the composite’s thermal stability. Moreover, the composite exhibited a favorable combination of enhanced mechanical strength and excellent elasticity. Full article

Absence epilepsy (AE) is a common pediatric epilepsy syndrome marked by brief lapses in consciousness and characteristic 2.5–4 Hz spike-and-wave discharges on EEG. Although its clinical and electrophysiological features are well established, the molecular mechanisms underlying AE remain incompletely understood. Proteomic approaches offer a powerful means to explore these mechanisms; however, their application in AE remains limited and methodologically heterogeneous, which complicates data integration. In this review, proteomic methodologies applied in rodent models of absence epilepsy are critically examined, including genetic rat models such as Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij), monogenic mutant mouse models, and pharmacologically induced models. The technical workflow is described particularly, from tissue sampling and protein preparation (including gel-based and gel-free methods) to mass spectrometric analysis using data-dependent and data-independent acquisition strategies. Emerging technologies such as spatial proteomics, Trapped Ion Mobility Spectrometry coupled with Parallel Accumulation–Serial Fragmentation (TIMS-PASEF), and the integration of artificial intelligence are also evaluated in relation to their potential to address current technical limitations. Beyond synthesizing convergent molecular pathways including synaptic dysfunction, altered energy metabolism, and neuroinflammation, the review examines how methodological choices—such as model selection, brain region dissection, sample preparation protocols, and analytical platforms—contribute to experimental outcomes and data interpretation. By integrating current evidence with a focus on methodological aspects, this review provides a framework for designing more robust, reproducible, and clinically relevant proteomic studies in absence epilepsy. Full article

To explore the function of the period gene (Ec-per) in Exopalaemon carinicauda, we cloned the gene of 4611 bp with a 5′UTR of 201 bp, a 3′UTR of 813 bp, and an ORF of 3597 bp encoding 1198 amino acids. The predicted protein includes two PAS and one PERIOD domain. qPCR analysis revealed that Ec-per was expressed across all tissues tested at different developmental stages and during both embryonic and larval stages. Moreover, Ec-per oscillated rhythmically under different conditions of light-to-dark (L:D) ratios, including continuous darkness (0 L:24 D), where changes in the photoperiod influenced amplitude and phase shifts. The knockdown of Ec-per mRNA significantly reduced the expression of the circadian-related genes timeless (tim) and cryptochrome 1 (cry1) (p < 0.05). This suggests that Ec-per is an endogenous clock gene that may participate in molecular feedback loops and synergistically regulate the circadian rhythms through interacting with tim and cry1. RNA interference of Ec-per also markedly downregulated ecdysone receptor mRNA (p < 0.05), suggesting a positive role in the ovarian development of E. carinicauda. In situ hybridization further demonstrated that Ec-per is involved in oocyte proliferation and the accumulation of exogenous nutrients. This study provides new insights for promoting ovarian development and artificial breeding in crustaceans through optimized light-cycle management. Full article

Breast cancer is the most common and deadliest cancer among women. While overexpression of specific markers guides disease stratification and has enabled the development of targeted therapies, identifying new therapeutic targets remains critical, particularly for aggressive subtypes lacking effective treatments. This study evaluated the expression of α-Lactalbumin (LALBA) and nucleolin (NCL) in breast cancer tissues from Mexican patients using gene expression analysis and immunohistochemistry. LALBA, a major milk protein normally expressed only during late pregnancy and lactation, was detected in nearly all tumor samples and showed higher levels in aggressive subtypes, with overexpression displaying a slight trend toward poorer overall survival. NCL, a multifunctional nucleolar protein, exhibited predominantly nuclear localization, with moderate expression associated with improved survival. Both proteins correlated with tumor immune features, including increased tumor-infiltrating lymphocytes (TILs) and PD-L1 expression for LALBA, and elevated CD8⁺ T cells, PD-L1, and TIM-3 expression for NCL. Overall, these findings suggest that LALBA and NCL are associated with tumor aggressiveness, immune context, and survival trends in breast cancer. Additional studies in larger cohorts are needed to define their clinical relevance. Full article

This paper presents a compact mixed-mode first-order universal filter based on a single voltage differencing current conveyor (VDCC), which can function in all four possible operation modes, i.e., voltage mode (VM), trans-admittance mode (TAM), current mode (CM), and trans-impedance mode (TIM). The proposed configuration requires only two grounded resistors and one floating capacitor, which contributes to a low component count, facilitates integration, and allows for the electronic tunability of the pole frequency through the transconductance gain of the VDCC. This work also demonstrates two practical biomedical applications: an electrocardiogram (ECG) acquisition system utilizing the VM low-pass filter for noise suppression and a bioimpedance (BioZ) measurement system employing the proposed configuration-based CM oscillator circuit as a sinusoidal excitation source. The performance validation confirms the accuracy of impedance extraction and the preservation of waveforms using tissue-equivalent models. The results demonstrate that the proposed VDCC-based filter offers a compact, power-efficient, and versatile analog signal-processing solution suitable for modern biomedical instrumentation. Full article

Immune checkpoint proteins including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT regulate T-cell functions, which are essential for anti-tumor immunity. Over-expression of these immune checkpoint proteins leads to T-cell exhaustion and a significant impairment of anti-tumor immunity. Rejuvenation of effector T-cell function with immune checkpoint inhibitors (ICI) restores anti-tumor immunity, which translates into clinical efficacy in the frontline and salvage treatment of various hematological malignancies. Efficacy of ICIs is highest in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and NK/T-cell lymphomas, and modest in immune-privileged-site lymphomas and cutaneous T-cell lymphoma. However, in myeloid malignancies and multiple myeloma, the efficacy of ICIs remains doubtful. In addition to being used as single agents, ICIs have also been combined with other ICIs; as well as chemotherapy, antibody drug conjugates, and epigenetic agents (histone deacetylase inhibitors and hypomethylating agents). More innovative strategies include the use of ICIs in the context of allogeneic haematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. This review synthesizes current evidence for the use of ICI in different haematological malignancies, and highlights future directions toward biomarker-driven, rationally designed therapeutic combinations. Full article

Background: Through the direct electrical stimulation of spiral ganglion neurons (SGNs) of the hearing nerve, cochlear implants overcome functionally impaired or missing hair cells in patients with profound to severe hearing loss. In routine clinical fitting, regions with severe local SGN degeneration (modiolar “dead regions”) cannot be identified. As a result, the electrical fields of neighboring electrodes are broadened, which can lead to increased channel interaction and, consequently, poorer speech understanding and hearing. The objective of this study was to ascertain whether neural health status can be evaluated by using cochlear implants’ inbuilt measures. Methods: Electrode impedance (MP1-, MP2-, MP1/MP2-, common ground mode), transimpedance matrix (TIM) and electrically evoked compound action potential (eCAP) measurements were performed before and after laser-induced induction of lesions on the modiolus of the guinea pig. Laser treatment-related shifts in impedance, TIM, and eCAP characteristics (threshold, amplitude, and a modified version of the failure index, referred to as the efficiency index (EI)) were correlated with the histologically assessed damage in three predefined areas of the basal modiolus within the electrode region. Results: Modiolar damage resulted in a significant reduction in the electrode impedance in MP2- and MP1/2-mode, the eCAP amplitude, and the EI. In contrast, TIM values and eCAP thresholds were significantly elevated. MP1, MP1/MP2 electrode impedance, TIM, and the eCAP thresholds were not correlated with the extent of modiolar damage. The shifts in eCAP amplitudes and the EI were significantly correlated with the damage at all regions of the basal modiolus. Conclusions: The eCAP amplitude and the EI are both capable of objectively evaluating the neural health status of the cochlea. Thus, a modiolar dead region could be expected from a local drop in eCAP amplitude values or the modified EI within the electrode array. Full article

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies before the 22nd gestational week and affects 10–15% of clinical pregnancies. Despite extensive diagnostics, over 50% of RPL cases remain unexplained, suggesting an important role for immunological mechanisms. Sex hormones (SH) are key regulators of immune responses during pregnancy; however, their influence on immune checkpoint proteins (ICPs) is poorly understood. This study evaluated the effects of progesterone, β-estradiol, and dihydrotestosterone (DHT) on ICP expression on immune cells, including Treg, NK, NKT, TC, Th, and T cells, collected from pregnant women and patients with unexplained RPL (uRPL). Peripheral blood mononuclear cells from 20 pregnant women and 20 uRPL patients were cultured for 48 h with SH. The expression of the first generation of ICPs—PD-1 and TIM-3—and the second—LAG-3, TIGIT, and VISTA—on T, NK, and NKT cells was analyzed by the flow cytometry method. In pregnant women, SH exerted modest effects, with DHT increasing VISTA and LAG-3 expression, while progesterone and estradiol mainly upregulated LAG-3 and TIM-3 on cytotoxic cells. In contrast, uRPL immune cells showed pronounced SH sensitivity, characterized by increased TIM-3 and VISTA expression and reduced TIGIT expression, particularly after DHT stimulation. In conclusion, SH modulates ICP expression in a cell-specific manner, with stronger effects observed in uRPL patients’ lymphocytes. These findings highlight a potential role for hormonal and ICP-targeted strategies in RPL management. Full article

Power converters based on gallium nitride (GaN) are progressing swiftly owing to their exceptional efficiency and tiny dimensions, boosted by high power density and fast switching capabilities. Nevertheless, these benefits are accompanied by considerable thermal management issues that impact reliability, performance, and operational lifespan. This review examines advanced thermal management approaches for high-power-density GaN power converters, including active and passive cooling technologies, sophisticated packaging designs, and the use of novel materials like graphene and diamond to improve heat dissipation. The impacts of thermal boundary resistance, self-heating phenomena, and substrate selection on thermal performance are thoroughly analyzed. Strategies for enhancing printed circuit board (PCB) layouts, thermal vias, and the use of thermal interface materials (TIMs) are also emphasized. The study highlights co-design approaches that optimize thermal resistance and layout efficiency, supporting GaN operation under high-frequency conditions. This thorough investigation offers insights into addressing the thermal challenges linked to GaN technology, promoting its adoption in forthcoming power devices. Full article