Search Results (2,431)

Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

This study investigated the impact of moderate teat-end hyperkeratosis on milk somatic cell count (SCC) and bacterial count (BC) in Holstein cows. Comparing teat-end scores (TS) 2 and 3, we found that TS3 quarters exhibited significantly higher SCC (p = 0.017) despite having shorter days in milk than TS2 quarters. While BC in foremilk (BC1) remained stable, post-milking samples (BC2) decreased during sequential sampling; however, a significant Group × Time interaction (p = 0.020) revealed a less pronounced bacterial reduction in TS3. These findings tentatively suggest that moderate hyperkeratosis (TS3) may be associated with subclinical mammary irritation and altered bacterial clearance dynamics, independent of the absolute bacterial load. Managing teat-end morphology may help optimize milk quality, even when bacterial contamination is minimal. Full article

This cross-sectional study assessed bulk-tank raw milk quality, subclinical mastitis burden, and farmers’ health management practices across 83 sheep and goat farms in the Epirus Region of northwestern Greece (October 2022–April 2023). Bulk-tank milk composition (fat 5.82%, protein 5.35%, lactose 4.82%) was consistent with Mediterranean small-ruminant norms. Mean somatic cell count (SCC) was 1123 ± 913 × 10³ cells/mL (median 883 × 10³); only 10.0% of farms met the healthy threshold (SCC ≤ 200 × 10³ cells/mL) and 26.2% exceeded the EU limit of 1500 × 10³ cells/mL (Regulation EC No 853/2004). SCC correlated positively with total bacterial count (Spearman ρ = 0.549, p < 0.001). Farmers were predominantly middle-aged (50.0 ± 11.8 years), exclusively male, and had low levels of formal education (9.0% university-educated); only 14.3% had regular veterinary support, and 34.9% practised post-milking teat dipping. Despite 51.3% self-reporting mastitis, no management or demographic variable was significantly associated with SCC after Bonferroni correction; education showed the strongest trend (Kruskal–Wallis H = 9.13, p = 0.058). The findings reveal widespread, largely undiagnosed subclinical mastitis driven by structural gaps in veterinary support, education, and hygiene practice, with direct implications for animal health and targeted advisory intervention. Full article

Mastitis is a major and costly dairy disease that reduces milk yield and quality and harms animal welfare. This study evaluated infrared thermography (IRT) combined with machine learning (ML) for non-invasive mastitis screening in dairy cows and explored links with biological and feeding-system variables in Egyptian farms. A total of 976 thermal udder images obtained from 488 Holstein cows were used, including 708 healthy and 268 mastitic images. Images were captured before milking, processed with CLAHE, resized to 224 × 224 pixels, and split using cow-level grouping before augmentation to prevent animal-level data leakage. The training set contained 780 original images and was augmented to a balanced 4708-image set (2354 per class), while the held-out test set remained unaugmented, with 196 original images (142 healthy and 54 mastitic). EfficientNetB3 with global average and max pooling extracted 3072 thermal features, and ten ML classifiers were evaluated. In the image-level hold-out evaluation, MLP achieved the best performance (accuracy = 86.22%, AUC = 0.9184, sensitivity = 74.07%, specificity = 90.85%), followed by SVM (accuracy = 83.67%, AUC = 0.8963). A separate group-based five-fold cross-validation yielded a more conservative AUC of 0.6812 ± 0.1323 and accuracy of 0.6244 ± 0.0642. Logistic regression analyses did not identify statistically significant associations between model predictions and somatic cell count (SCC), California Mastitis Test (CMT), blood biomarkers, or nutritional variables at p < 0.05. Ration A (Delta Misr) showed a higher observed mastitis incidence (20/40; 50.0%) than Ration B (Copenhagen; 16/45; 35.6%), but nutritional predictors were not statistically significant, indicating that farm-level confounding should be considered. Overall, IRT with ML remains a promising non-invasive screening approach, but broader multicenter datasets and independent external validation are needed before routine farm deployment. Full article

Objective: Subjective cognitive complaints (SCC) and neuropsychiatric symptoms (NPS) are both recognized as early markers of dementia, but their combined predictive value is not well understood. This study investigated whether SCC and NPS, individually and jointly, predicted six-year cognitive decline and 12-year incident dementia in community-dwelling older adults. Methods: Participants were 468 dementia-free individuals aged 70–90 from the Sydney Memory and Ageing Study, followed for up to 12 years. Cognitive decline was assessed biennially via neuropsychological tests; dementia diagnoses were made by expert consensus. SCC were captured using two self-reported and one informant-reported item. NPS were assessed using the informant-rated Neuropsychiatric Inventory. SCC and NPS were each operationalised as ordinal scores ranging from 0 to 3, with higher scores reflecting more SCC items or more NPS clusters, respectively, and participants were categorized into SCC−/NPS−, SCC+/NPS−, SCC−/NPS+, SCC+/NPS+. Linear regression models assessed associations with six-year cognitive decline across domains and global cognition, and Cox proportional hazards models assessed incident dementia risk over 12 years. Results: SCC sum scores predicted dementia risk, whereas NPS sum scores were not significantly associated with dementia risk. In the combined SCC/NPS group analyses, SCC+/NPS+ participants had a 66% higher hazard of dementia (HR = 1.66, p = 0.041). For cognitive decline, the SCC−/NPS+ group showed significantly greater decline in executive function, visuospatial ability, and global cognition compared with SCC−/NPS−. Neither SCC+/NPS− nor SCC+/NPS+ predicted domain-specific decline. Discussion: SCC and NPS showed different patterns of association with later outcomes, with the combined SCC/NPS profile identifying a subgroup at elevated dementia risk. These findings support closer monitoring of older adults who present with co-occurring SCC and NPS, as this profile may help improve early identification of individuals at risk of adverse cognitive outcomes. Full article

Background: Cutaneous squamous cell carcinoma (cSCC) is commonly regarded as a sporadic malignancy primarily driven by ultraviolet exposure. However, the occurrence of multiple, aggressive tumors at a relatively young age suggests the presence of underlying genetic susceptibility. The role of germline variants affecting extracellular matrix organization, pigmentation pathways, and tumor metabolism in aggressive cSCC remains incompletely understood. Case Presentation: We describe a 53-year-old patient with a long-standing history of multiple aggressive cutaneous squamous cell carcinomas involving the scalp and facial regions, characterized by recurrent and multifocal disease. A comprehensive diagnostic approach was undertaken, including histopathological examination, fluorescence confocal microscopy, high-frequency cutaneous ultrasound, and genetic analysis using whole-exome sequencing (WES). Results: Histopathology confirmed high-risk features consistent with aggressive cSCC. Cutaneous ultrasound and fluorescence confocal microscopy provided complementary, non-invasive insights into tumor depth, architecture, and invasive patterns. Whole-exome sequencing identified a heterozygous truncating variant in COL6A3 (NM_004369.4:c.5645C>A, p.Ser1882Ter), classified as likely pathogenic according to ACMG criteria. Additionally, two heterozygous variants of uncertain significance were detected in TYR (NM_000372.5:c.1569C>A, p.Ser523Arg) and FH (NM_000143.4:c.1237-5_1237-4insTCTCCCTCCCTC). Although individually inconclusive, the combined germline genetic background may have contributed to the patient’s aggressive and multifocal cutaneous phenotype. Discussion: This case report supports a potential role of extracellular matrix remodeling, pigmentation-related susceptibility, and metabolic dysregulation in cutaneous carcinogenesis and tumor aggressiveness. This case illustrates how integrating WES with advanced non-invasive imaging techniques can enhance the understanding of biologically aggressive cSCC. Conclusions: This report highlights a unique case of multifocal aggressive cSCC characterized by a distinct germline genetic profile identified by WES and multimodal imaging assessment. Comprehensive molecular and imaging evaluation may be beneficial in selected patients with atypical or aggressive cutaneous squamous cell carcinoma, with implications for personalized surveillance and management. Full article

This study presents a multiscale investigation of cement-based systems modified with silica fume (SF) and fly ash (FA) for self-compacting concrete (SCC). Cement pastes and mortars with replacement levels of 0%, 5%, 10%, and 15% were evaluated for rheological behavior, hydration kinetics, and microstructural evolution using rotational rheometry, semi-adiabatic calorimetry, scanning electron microscopy, and X-ray diffraction. The results show that SF increases plastic viscosity and promotes structural build-up due to its high specific surface area and pozzolanic reactivity, while its influence on yield stress depends on dispersion conditions and superplasticizer efficiency. In contrast, FA reduces both yield stress and viscosity, improving flowability due to its spherical particle shape. Thermal analysis indicates that SF modifies hydration by reducing and slightly delaying the main exothermic peak at higher dosages, whereas FA mainly lowers the peak temperature with limited effect on its timing. Microstructural analysis reveals that SF contributes to a denser, more homogeneous matrix through pore refinement and increased C–S–H formation, whereas FA systems exhibit a more heterogeneous structure with slower early-age development. The results demonstrate a clear relationship between rheology, hydration, and microstructure. The combined use of SF and FA has been shown to be an effective approach to improving the performance and sustainability of SCC. Full article

This paper addresses the critical challenge of identifying cost-effective coalitions of social media influencers to promote environmental sustainability (ES) messages under budget constraints. Traditional influencer marketing often relies on heuristics that ignore relational dependencies and heterogeneous agent costs, leading to redundant coverage and suboptimal resource allocation. To overcome these limitations, we introduce a novel Relational Cooperative Game (RG) framework that formalizes pre-determined dependencies among influencers and followers using closure operators, enabling a portfolio of polynomial-time identification algorithms for Minimal Winning Coalitions (MWCs). We further extend this model to the Weighted Cost-Relational Game (WCRG) to optimize campaigns with heterogeneous influencer costs. We prove that finding a Minimum-Cost Winning Coalition (MCWC) is NP-hard via reduction from weighted set cover and propose two complementary algorithms: (1) a Greedy Cost–Benefit (GCB) algorithm that operates in polynomial time and empirically achieves optimal solutions across all tested instances; a logarithmic approximation guarantee is established for the restricted single-antecedent model; and (2) an Integer Linear Programming (ILP) formulation enhanced with Strongly Connected Component (SCC) preprocessing to handle cyclic dependencies and yield exact optimal solutions for moderate instances. Extensive empirical validation, ranging from a representative six-agent cyclic scenario to large-scale synthetic networks (up to 300 agents), confirms the framework’s robustness and scalability. Results demonstrate that GCB consistently achieves optimal solutions (approximation ratio = 1.000×) with subsecond runtime (<0.2 s) and minimal memory overhead (<50 MB), while ILP-SCC leverages graph condensation for rapid exact solving. Compared to size-based baselines, WCRG achieves up to 95.2% cost savings by systematically leveraging cost-efficient micro-influencers, empirically validating that minimizing coalition size does not guarantee cost efficiency. These findings establish WCRG as a scalable, budget-aware optimization toolkit for maximizing the impact of sustainability campaigns through relational coalition design. Full article

Air entrainment in self-compacting concrete (SCC) is governed by coupled interactions between chemical admixtures, empirical workability behaviour, aggregate-skeleton geometry and early air-bubble stability. In highly flowable mixtures, the hardened air-void system cannot be assessed reliably from total air content alone because bubble escape, redistribution and coalescence in the fresh state may change the final pore structure. This study evaluates the link between early fresh-air retention and hardened air-void characteristics in 25 SCC mixtures arranged according to a five-level Graeco-Latin square design. The analysed factors were air-entraining admixture (AEA) dosage (0.00–0.20% by mass of cement), binder type, water-to-binder ratio (0.29–0.41) and the volumetric paste-to-aggregate filling parameter φ (1.1–1.5). The aggregate skeleton was kept constant to separate paste-composition and volumetric-filling effects from aggregate grading. Fresh concrete was characterised by slump-flow diameter, T₅₀ flow time, density and air content after 5 and 15 min; these quantities were treated as empirical workability and early-retention indicators, not as direct rheological parameters. Hardened concrete was examined after 28 days according to EN 480-11 using total hardened air content A, spacing factor L, micropore content A₃₀₀ and specific surface α. The slump-flow diameter ranged from 50 to 79 cm, fresh air content after 5 min from 1.6% to 8.6%, air loss between 5 and 15 min from 0.41 to 1.12 percentage points, hardened air content from 1.20% to 8.59%, and spacing factor from 0.13 to 0.44 mm. Strong correlations were obtained between fresh and hardened air contents (A₅ vs. A: r = 0.920, R² = 0.846, p < 0.001, 95% CI for r: 0.824–0.964; A₁₅ vs. A: r = 0.922, R² = 0.849, p < 0.001, 95% CI for r: 0.828–0.965), while hardened air content was strongly and inversely related to spacing factor (A vs. L: r = −0.907, R² = 0.822, p < 0.001, 95% CI for r: −0.958 to −0.797). The recalculated ANOVA showed that statistical significance was response-dependent: w/b was significant for early air loss ΔA (F = 4.190, p = 0.040, partial η² = 0.677) and micropore content A₃₀₀ (F = 4.058, p = 0.044, partial η² = 0.670), whereas binder type showed near-threshold tendencies for fresh and hardened air contents. No single factor was statistically significant for all air-void descriptors. The SDI-based approach is therefore presented as a bounded explanatory framework, not as an externally validated prediction model. Direct durability claims, including freeze–thaw resistance, require separate experimental verification. Full article

Background/Objectives: Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional small molecules that induce ubiquitin–proteasome–mediated degradation of target proteins and have matured from proof-of-concept chemistry to a clinically validated therapeutic modality, with the first Phase 3 readout reported in 2025. A systematic bibliometric analysis covering this pivotal-trial era, however, has been lacking. This study aimed to map the historical trajectory, current research front, and emerging frontiers of PROTAC research. Methods: We analyzed 2630 PROTAC-related publications indexed in the Web of Science Core Collection (WoSCC) from 2001 to 2025 using a combined toolkit of CiteSpace, HistCite, the Alluvial Generator, and R (ggplot2), covering co-occurrence networks, burst detection, keyword clustering, citation historiography, alluvial flow analysis, and reference co-citation timeline visualization. Results: China and the USA led global output, and the Chinese Academy of Sciences, China Pharmaceutical University, and Harvard University were the most productive institutions; the Journal of Medicinal Chemistry was the leading publishing venue, and Alessio Ciulli, Jian Jin, and Craig M. Crews anchored the author network. Keyword burst analysis showed that early research centred on E3 ubiquitin ligase recruitment and small-molecule PROTAC design, whereas the current hotspots, resolved through keyword clustering and co-citation timelines, included structural basis and ternary complex design, EGFR-directed degradation, oral bioavailability optimization, applications in multiple myeloma and Alzheimer’s disease, tumour-targeted delivery, and computational/AI-driven design. Conclusions: This study extends the bibliometric record of PROTACs across 2001–2025 and identifies oral bioavailability, E3 ligase repertoire expansion, and CNS-penetrant degrader design as the emerging frontiers likely to shape the next phase of the field. Full article

Background: Measles, mumps, rubella (MMR) and varicella vaccines are often co-administered to optimize coverage, yet safety concerns regarding febrile convulsions persist. In South Korea, MMR and varicella vaccines are administered as separate injections during a single visit (MMR + V). This study evaluated the real-world safety of concurrent MMR + V vaccination, focusing on the domestically implemented MAV/06 and Oka-derived strains. Methods: We conducted a multicenter self-controlled case series (SCCS) study of children aged 12–23 months who received MMR + V and hepatitis A vaccine (HAV) between 2015 and 2024. Using electronic health records, we identified predefined adverse events (AEs), including fever and healthcare visits. Adjusted relative risks (aRRs) were estimated using conditional Poisson regression. Results: Among 3035 children (52.3% male; median age, 12 months), 71.7% received the MAV/06 varicella strain. A distinct peak in AEs occurred 7–13 days after MMR + V administration, with fever showing the greatest increase (aRR, 4.27; 95% CI, 2.76–6.60). The risks of total sick visits (aRR, 2.15; 95% CI, 1.70–2.71) and acute care visits (aRR, 2.13; 95% CI, 1.46–3.10) were similarly confined to this interval and returned to baseline thereafter. Febrile convulsions were uncommon (aRR, 5.37; 95% CI, 1.20–24.01). No excess risks were observed during the HAV or overlap periods, and no synergistic effects of intensive multi-vaccine administration were detected. Conclusions: Concurrent administration of MMR and varicella vaccines in Korean infants—predominantly using the MAV/06 strain—was associated only with expected, transient increases in fever during days 7–13 postvaccination. No serious or sustained safety signals were identified, supporting the continued use of Korea’s separate-injection MMR + V strategy. Full article

Self-compacting concrete (SCC) is widely adopted in complex structural engineering due to its excellent flowability and filling capacity. However, in harsh corrosive environments, its complex internal pore structure can easily serve as a preferential pathway for the transport of aggressive media, leading to durability deterioration. This study systematically investigates the effects of chemical attack inhibitor (CAI) on the workability, mechanical properties, sulfate attack resistance, and chloride ion penetration resistance of SCC. The micro-mechanisms governing pore structure evolution are elucidated using low-field nuclear magnetic resonance (LF-NMR) and X-ray computed tomography (X-CT). At a CAI dosage of 2%, the fresh SCC exhibits a slump of 260 mm and slump flow of 720 mm, indicating excellent filling and gap-passing abilities. Meanwhile, the compressive strengths at 3 d, 7 d, and 28 d remain at a high level. After 120 sulfate wet-dry cycles, the strength loss rate is only 8.4%, with an erosion resistance coefficient exceeding 90%. In addition, the resistance to chloride ion penetration is significantly improved, with an electric flux of only 1331 C, which is considerably lower than that of the control group (1637 C). At the optimal dosage of CAI, the concrete exhibits a dense and uniform internal structure devoid of macroscopic defects or cracks, with minimized porosity, thus synergistically enhancing the resistance to sulfate attack and chloride attack. On the contrary, further increasing the CAI dosage markedly intensifies the inhibitory effect of organic components on cement hydration, leading to increased early-age defects and enhanced pore connectivity. Thus, an appropriate amount of CAI can effectively improve the overall performance of SCC, providing a solid experimental basis and theoretical support for its engineering application in harsh corrosive environments. Full article

Ultraviolet (UV) light exposure is a recognised risk factor for dermal haemangiosarcoma (HSA) in dogs and dermal squamous cell carcinoma (SCC) in dogs and cats. These tumours cause substantial local disease and often require repeated surgery due to recurrence or de novo lesions, creating a notable welfare and financial burden. Research on preventing harmful UV exposure in pets is still in its infancy, particularly in relation to the safety of UV filters used in sunscreens. This review summarises the current evidence on UV-induced carcinogenesis, strategies to reduce UV exposure, and the safety of sunscreen ingredients in dogs and cats. UV light is strongly implicated in a range of dermatoses, from actinic keratosis to dermal HSA and SCC in dogs and cats, and the risk is likely higher in Australian pets. Indoor confinement during peak UV periods, shade, and sun-protective clothing can reduce exposure, with sunscreen an additional strategy. Sunscreen is relevant because UV-associated cancers typically develop in sparsely haired or hairless regions such as the nose and ventrum, making these areas suitable for targeted sunscreen application. Sunscreens containing non-nanoparticle zinc oxide appear safe for dogs and cats when ingestion is prevented or minimised, whereas the safety of organic UV filters remains unclear due to limited safety data in both humans and animals. Non-nanoparticle titanium dioxide is a possible alternative to zinc oxide and organic filters, but there is currently little information on its safety when ingested by dogs and cats. Overall, the available evidence supports sunscreen as a necessary component of UV-reduction strategies in pets, but substantial research is needed to determine the safety profiles of different UV filters and to establish evidence-based guidelines for their safe use. Full article

Hyperspectral image (HSI) and LiDAR data fusion is valuable for land-cover classification in complex surface scenes. Existing methods typically extract features from each modality independently and then consider how to fuse them, ignoring the semantic consistency between features of different modalities and across different hierarchical levels. Moreover, fully mining and exploiting the complementary information between multimodal remote sensing data remains a critical issue. To address these challenges, this paper proposes a hierarchical semantic consistency constraint (HSCC) framework for HSI and LiDAR data joint classification. The framework is co-constructed by a progressive interactive fusion network (PIFNet) and a semantic consistency constraint (SCC) strategy. Specifically, PIFNet progressively calibrates the semantic representations of multimodal features at different abstraction levels through Cross-Modal Shared Attention and Symmetric Cross-Attention mechanisms, promoting information parity in deep interactions. The SCC strategy establishes multi-level semantic associations and employs a semantic consistency constraint loss to guide the network to autonomously maintain the consistency of the same land-cover object across heterogeneous feature representations, thereby further enhancing the discriminative power of the fused features. Experiments on three public datasets, MUUFL, Houston2013, and Augsburg, demonstrate that HSCC outperforms current state-of-the-art methods, validating its effectiveness in multi-source remote sensing data fusion classification tasks. Full article

Matrilysins and stromelysins play a vital role in cancer, facilitating tumor invasion and metastasis. The aim of this study was to investigate the diagnostic significance of selected matrilysins and stromelysins in comparison to routine tumor markers in gynecological malignancies, relative to a control group (benign tumors and healthy women). Preoperative plasma levels of selected metalloproteinases were determined using ELISA, while levels of CA125, SCC-Ag, and HE4 by CMIA. In endometrial and cervical cancers, matrilysins (MMP-7 and MMP-26) exhibited higher diagnostic utility than routine markers. Similarly, all stromelysins in cervical cancer outperformed CA125; furthermore, MMP-10 also outperformed SCC-Ag, achieving the highest diagnostic utility among all parameters tested in cervical cancer. For ovarian cancer, diagnostic utility remained highest for routine markers. In endometrial and cervical cancers, the AUCs for all studied parameters exceeded those of standard markers, while in ovarian cancer, MMP-7 had an AUC higher than HE4 and comparable to CA 125. Combined analysis of the studied parameters in diagnostic panels demonstrated that their introduction into routine diagnostics could provide tangible benefits in the detection of malignant gynecological lesions, especially the combination of MMP-7 or MMP-10 with routine markers. These results indicate the usefulness and high diagnostic power of selected MMPs in the detection of these malignancies. Full article