Search Results (322)

The article presents the current state of knowledge on genetic modifiers of ovarian cancer risk in women carrying pathogenic variants (PVs) in the BRCA1 and BRCA2 genes, which are major contributors to hereditary susceptibility to this malignancy. Although PV carriers have high disease penetrance (BRCA1: ~40% and BRCA2: 11–27%), substantial variability in individual risk is observed, suggesting the influence of additional genetic variants. Background: Ovarian cancer is characterized by late detection and high mortality, and a significant portion of risk among BRCA1/2 carriers is shaped by reproductive and environmental factors as well as genetic modifiers. The article emphasizes that carriers of the same BRCA PV can exhibit markedly different risk levels depending on additional variants that modulate key biological processes, such as DNA repair, cell cycle regulation, and apoptosis. Methods: A systematic literature search covering the years 1996–2025 was conducted in the PubMed database. Initially, 734 publications were identified; after removing duplicates, thematically irrelevant articles, non-full-text papers, and studies not meeting the inclusion criteria, 47 articles were included in the review. These studies covered candidate gene analyses, GWAS, and data from the CIMBA consortium, which enables the examination of large cohorts of PV carriers. Results: The review identified numerous variants associated with increased or decreased ovarian cancer risk in BRCA1 carriers, including the following: OGG1, DR4, MDM2, CYP2A7, CASP8, ITGB3, HRAS1, TRIM61, and MTHFR. The reviewed studies also identified both protective and risk-increasing variants among BRCA2 PV carriers: UNG, TDG, and PARP2, and haplotypes in ATM, BRIP1, BARD1, MRE11, RAD51, and 9p22.2. The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP. Protective variants include BNC2 and LINC00824. The only SNP reaching genome-wide significance (p < 5 × 10⁻⁸) was in BNC2. Conclusions: The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets. Full article

Significant differences in reproductive performance exist between meat-type ducks (e.g., Qiangying Duck, QD) and laying-type ducks (e.g., Shaoxing Duck, SD). The molecular mechanisms underlying these differences, particularly concerning ovarian development and function, remain incompletely understood. This study aimed to comprehensively characterize the ovarian transcriptomes of these two duck types, focusing on differential gene expression and post-transcriptional regulatory events. We performed an integrated full-length transcriptome analysis of ovarian tissues from these two breeds using PacBio SMRT and Illumina sequencing. Bioinformatic analyses, including functional annotation, differential expression analysis, and the identification of APA events, were used. We discovered substantial breed-specific differences in alternative polyadenylation (APA), with SD ducks exhibiting significant 3′UTR shortening in 3799 genes and 3′UTR lengthening in 1626 genes compared to QD. The integrated analysis of differential gene expression and APA events highlighted key genes related to steroid hormone synthesis (HMGCS1, DHCR24), lipid metabolism (SCD), signal transduction (HRAS), and antioxidant defense (SOD1). The functional enrichment implicated critical pathways such as mitochondrial energy metabolism, oxidative phosphorylation, and fatty acid degradation. Our study provides a comprehensive atlas of post-transcriptional regulation in the duck ovary and reveals APA as a crucial process of gene regulation. APA may contribute to the differential ovarian function and egg-laying capacity between meat and laying ducks, thus offering valuable targets for genetic selection. Full article

Sharp declines in temperature pose a significant risk for mass mortality events in the Chinese soft-shelled turtle (Pelodiscus sinensis). To assess the effects of acute cold stress on intestinal health, turtles were exposed to temperatures of 28 °C (control), 14 °C, and 7 °C for 1, 2, 4, 8, and 16 days. The results showed that acute cold stress at 14 °C and 7 °C induced time-dependent alterations in intestinal morphology and histopathology. The damage was more severe at 7 °C, characterized by inflammatory cell infiltration, lymphoid hyperplasia, and extensive detachment and necrosis across the villi, muscle layer, and submucosa. 16S rDNA sequencing revealed significant shifts in intestinal microbiota composition in the 7 °C group, dominated by Helicobacter and Citrobacter. Transcriptomic analysis identified differentially expressed genes (DEGs) that respond to acute cold stress and are involved in the Toll-like receptor signaling pathway (Tlr2, Tlr4, Tlr5, Tlr7, and Tlr8), the NOD-like receptor signaling pathway (Traf6, Traf2, Casr, Rnasel, Pstpip1, Plcb2, Atg5, and Mfn2), apoptosis (Tuba1c, Ctsz, Ctsb, Kras, Hras, Pik3ca, Bcl2l11, Gadd45a, Pmaip1, Ddit3, and Fos), and the p53 signaling pathway (Serpine1, Sesn2, Ccng2, Igf1, Mdm2, Gadd45a, Pmaip1, and Cdkn1a). Metabolomic profiling highlighted differentially expressed metabolites (DEMs) that cope with acute cold stress, such as organic acids (oxoglutaric acid, L-aspartic acid, fumaric acid, DL-malic acid, and citric acid) and amino acids (including L-lysine, L-homoserine, and allysine). The integrated analysis of DEGs and DEMs underscored three key pathways modulated by acute cold stress: linoleic acid metabolism, neuroactive ligand–receptor interaction, and the FoxO signaling pathway. This study provides a comprehensive evaluation of intestinal health in Chinese soft-shelled turtles under acute cold stress and elucidates the underlying mechanisms. Full article

Hyperspectral imaging (HSI) captures the same scene across multiple spectral bands, providing richer spectral characteristics of materials than conventional RGB images. The spectral reconstruction task seeks to map RGB images into hyperspectral images, enabling high-quality HSI data acquisition without additional hardware investment. Traditional methods based on linear models or sparse representations struggle to effectively model the nonlinear characteristics of hyperspectral data. Although deep learning approaches have made significant progress, issues such as detail loss and insufficient modeling of spatial–spectral relationships persist. To address these challenges, this paper proposes the Cascaded Multi-Attention Feature Recurrent Enhancement Network (CMFREN). This method achieves targeted breakthroughs over existing approaches through a cascaded architecture of feature purification, spectral balancing and progressive enhancement. This network comprises two core modules: (1) the Hierarchical Residual Attention (HRA) module, which suppresses artifacts in illumination transition regions through residual connections and multi-scale contextual feature fusion, and (2) the Cascaded Multi-Attention (CMA) module, which incorporates a Spatial–Spectral Balanced Feature Extraction (SSBFE) module and a Spectral Enhancement Module (SEM). The SSBFE combines Multi-Scale Residual Feature Enhancement (MSRFE) with Spectral-wise Multi-head Self-Attention (S-MSA) to achieve dynamic optimization of spatial–spectral features, while the SEM synergistically utilizes attention and convolution to progressively enhance spectral details and mitigate spectral aliasing in low-resolution scenes. Experiments across multiple public datasets demonstrate that CMFREN achieves state-of-the-art (SOTA) performance on metrics including RMSE, PSNR, SAM, and MRAE, validating its superiority under complex illumination conditions and detail-degraded scenarios. Full article

Objective(s): To delineate the somatic mutational landscape of follicular thyroid carcinoma (FTC) from a large, real-world cohort to identify molecular subtypes and actionable targets for personalized therapeutic interventions. Methods: Genomic and clinical data for 168 FTC samples were retrieved from the AACR Project GENIE^® registry via cBioPortal. This study assessed mutation frequencies, copy number alterations, and subgroup differences (primary vs. metastatic; adult vs. pediatric) using statistical tests. Results: NRAS was the most common mutation (33.9%), followed by TERT (22.6%), DICER1 (15.5%), HRAS (11.9%), and PTEN (10.7%). DICER1 mutations were significantly enriched in pediatric cases (44.4% vs. 4.6% in adults, p < 0.001), while TERT mutations were exclusive to adults (42%). NRAS mutations were more frequent in metastatic tumors (42.4%) than primary tumors (29.2%). Conclusions: FTC tumorigenesis is driven by distinct molecular pathways, with significant heterogeneity between pediatric and adult patients as well as primary and metastatic disease. These findings underscore the necessity of molecular profiling for patient stratification and provide a strong rationale for developing personalized treatment strategies to improve clinical outcomes. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) often presents at an advanced stage; therefore, the early detection of precursor lesions is crucial. However, the risk assessment of precursor lesions such as oral epithelial dysplasia (OED) remains challenging because of the subjectivity of histopathological grading. We aimed to identify molecular markers that enhance the diagnostic accuracy and prognostic stratification of OSCC and explore the differences in the molecular characterization of OED and OSCC using a few selected markers. Methods: A two-step diagnostic workflow was applied: (1) FISH evaluation of EGFR amplification and CDKN2A deletion to distinguish OED from OSCC and identify EGFR-dependent tumors, and (2) HRAS immunohistochemistry performed exclusively in EGFR-negative OSCCs to stratify EGFR-independent cases. Fluorescence in situ hybridization (FISH) was used to assess seven EGFR/cell cycle-related genes (CCND1, CDKN2A, EGFR, PIK3CA, PTEN, TP53, and 1p36 locus) in 117 formalin-fixed paraffin-embedded samples (66 OED and 51 OSCC) and 10 normal mucosa samples. HRAS expression was evaluated using immunohistochemistry (IHC) in 36 EGFR amplification-negative OSCCs samples. Results:EGFR amplification was frequent in OSCC, whereas CDKN2A deletion was common in OED. The EGFR-amplified/ CDKN2A-intact profile showed high specificity for OSCC and improved diagnostic performance (area under the curve = 0.77) when combined with the Ki-67 labeling index. It also predicted poor disease-free survival (hazard ratio [HR] = 5.08, p = 0.016) and overall survival (HR = 6.10, p = 0.047). Among EGFR-negative OSCCs, HRAS overexpression was associated with advanced-stage disease and a poor prognosis (HR = 6.15, p = 0.043). Conclusions:EGFR amplification was frequent in OSCC, and CDKN2A deletion was prevalent in OED, supporting their use as molecular markers for differential diagnoses. FISH for EGFR/CDKN2A and HRAS IHC can stratify OSCC by diagnosis and prognosis, enabling practical molecular subclassification, including EGFR-negative cases. Full article

Actinidia valvata, a promising rootstock for kiwifruit cultivation, demonstrates superior waterlogging tolerance compared with commercial cultivars. Lateral organ boundaries domain (LBD) transcription factors (TFs) are known to be pivotal in plant responses to abiotic stress. Nevertheless, the characterization of the LBD family under waterlogging stress in A. valvata remains limited. In this study, 26 AvLBD genes were identified from a transcriptome dataset, with the majority classified into phylogenetic Class II. Under waterlogging stress, transcript accumulation of most AvLBD41 members, particularly AvLBD41_11 and AvLBD41_7, was markedly increased in roots. Bimolecular fluorescence complementation (BiFC) assays indicated that AvLBD41_7 heterodimerizes with both the AP2/ERF activator AvERF75 and the trihelix repressor AvHRA1, whereas AvLBD41_11 only interacts with AvERF75. Neither AvLBD41 isoform interacts with AvERF73, thereby defining distinct components of a waterlogging-responsive module. Yeast-based assays revealed an absence of transactivation activity for AvLBD41_7, and transient expression analyses confirmed its exclusive nuclear localization. The promoters of both AvLBD41_11 and AvLBD41_7 harbor numerous cis-elements responsive to hormones and abiotic stresses. An AvLBD41_7-derived PCR marker could be used to distinguish A. valvata from A. deliciosa accessions. Collectively, these findings provide a comprehensive functional annotation of the LBD gene family in A. valvata and establish AvLBD41_7 as a potential molecular target for future kiwifruit breeding programs aimed at waterlogging resilience. Full article

Anal cancer is high in men who have sex with men living with human immunodeficiency virus (MSM-LWHIV). This cancer is strongly associated with high-risk human papillomavirus (HR-HPV) infection. Anal cancer screening using cytology and high-resolution anoscopy (HRA) for diagnosis of anal intraepithelial neoplasia requires specialized expertise. Biomarkers for the diagnosis of abnormal anal cells are of interest. Thyrotropin-releasing hormone (TRH) methylation at cg01009664 was detected using a pyrosequencing assay to compare methylation patterns among different anal lesions. Our results demonstrated that TRH methylation was significantly hypermethylated in anal intraepithelial neoplasia (AIN3) (>20%) and AIN1-2 (>10%) but less methylated in normal (<10%) (p < 0.001). TRH gene methylation showed higher sensitivity than the cytology for predicting AIN1+ (75.96% vs. 25.37%, respectively) and AIN2+ (78.95%% vs. 19.23%, respectively). There was no significant correlation between TRH methylation and the percentage of CD4 in patients with HIV (p > 0.05). TRH methylation in anal swabs reflects the presence of anal intraepithelial neoplasia. Methylation analysis showed higher sensitivity than cytology for high-grade lesions and was independent of immune status. These findings support its use as a screening tool to preselect patients for HRA, potentially reducing unnecessary procedures while maintaining diagnostic accuracy. Full article

Background: Healthcare burnout is pervasive, necessitating more efforts to reduce it. Objective: To evaluate the effectiveness of well-being leadership training in reducing healthcare burnout. Design: The Clinician Wellness Council (CWC) leadership training consisted of 15 months of educational and small group sessions (September 2023–November 2024) with pre–post-training burnout survey comparison. Setting: Primary and specialty departments across a Pacific Northwest community-based hospital system. Participants comprised 22 clinicians from primary and specialty departments. Participants identified an intervention group where they would focus their leadership efforts. Those groups contained 549 clinicians, and 5439 non-intervention clinicians were controls. Intervention: Well-being leadership training. Measures: The Maslach Burnout Inventory (MBI) and the turnover intent questions before and after training. Results: Of the 22 CWC participants, 15 (68%) completed the surveys before and after training. Burnout reduction was seen (47% to 13%; p = 0.0253), primarily driven by decreased emotional exhaustion (EE). Among 549 intervention group clinicians, 173 completed both surveys compared to 359 of 5439 clinicians in the control group. Intervention practitioners (N = 173) showed reductions in EE items (e.g., feeling burnout, working too hard, working with people is stressful) and turnover intent. Multivariable regression analyses showed that EE reductions were associated with co-workers’ intent to leave. Limitations: We obtained pre- and post-training MBI measures on a subset of the intervention group co-workers rather than a majority. Conclusions: Participation in a well-being leadership training program consisting of education, coaching, and community building reduced burnout, increased confidence to improve their workplace, and their leadership decreased co-worker EE and turnover intent. This training creates a blueprint for reducing burnout in clinician leaders and co-workers. Primary Funding Source: A PPMC foundation grant sponsored 10 local participants. Central division funding came from system and local funds. Participants received $1000/month training reimbursement. Full article

The RAS family of oncoproteins (KRAS, HRAS, and NRAS) drive aggressive cancers like pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), yet targeting mutant RAS has historically been challenging due to its “undruggable” structure. Recent advances in mutation-specific inhibitors (e.g., sotorasib for KRAS^G12C) have demonstrated clinical efficacy but face limitations in tumor types like PDAC, where KRAS^G12C mutations are rare. Broad-spectrum pan-RAS inhibitors (e.g., RMC-7977, RMC-6236, ADT-007/ADT-1004) now offer promise by targeting active GTP-bound or nucleotide-free RAS across isoforms and mutations. Preclinical studies show these agents induce deep tumor regressions, overcome resistance to allele-specific inhibitors, and remodel the tumor microenvironment (TME) by enhancing T-cell infiltration and reducing immunosuppressive myeloid cells. Early clinical data for RMC-6236 report disease control rates of 85–87% in NSCLC and PDAC, with manageable toxicity. This review shows that pan-RAS inhibitors represent a promising new class of therapeutics capable of overcoming many historical challenges associated with the “undruggable” nature of RAS proteins and demonstrating encouraging preclinical and early clinical results, particularly in difficult-to-treat tumor types such as PDAC and NSCLC. Challenges remain in achieving a therapeutic index due to RAS’s role in normal tissue homeostasis, but tumor-specific drug accumulation and rapid normal tissue recovery may mitigate risks. Ongoing trials are evaluating combination strategies with immunotherapy and chemotherapy, positioning pan-RAS inhibitors as transformative agents for RAS-driven cancers. Full article

Background: Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. Methods: 359 tumor samples from 346 patients with angiosarcoma were identified from the AACR Project GENIE v18.0-public database using cBioPortal. Somatic mutations and copy number alterations were assessed. Statistical significance was assessed by t-test for continuous variables and a chi-squared test for categorical data, with significance set at p < 0.05. Results: Recurrent mutations included TP53 (20.6%), KDR (13.6%), and PIK3CA (10.6%). Copy number alterations occurred in MYC (27.3%), CRKL (10.4%), FLT4 (5.5%), and KDR (4.8%). Homozygous deletions occurred in CDKN2A (6.6%), CDKN2B (6.56%), and MTAP (3.81%). Significant co-occurrence included FAT1-NOTCH2, TP53-ATRX, and NOTCH1-ARID1A. Mutual exclusivity was seen with KDR-FLT4 and KDR-ATRX. Females exhibited enrichment in MYC and HRAS, while males exhibited enrichment in POT1, NTRK2, and FAT1. Compared with primary tumors, metastatic tumors more often displayed ZFHX4, FGFR1, MSI2, HIST1H1C, and TOP1 mutations, while MAPK7 mutations occurred only in primary tumors. Conclusions: In one of the largest genomic analyses of angiosarcoma to date, we identified recurrent alterations, suggesting potential future therapeutic targets. Full article

Despite the growing use of collaborative robots in high-rise construction, ensuring safe human–robot collaboration (HRC) in hazardous environments remains a critical challenge. Addressing the gap that previous studies optimized human, robot, or task factors in isolation without a systemic coordination perspective, this study develops and empirically validates a Human–Task–Robot Alignment (HTRA) framework to explain how alignment mechanisms enhance safety performance in the construction of HRC. Data from 84 high-rise HRC projects were analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM). The results reveal that HTRA serves as a pivotal mechanism for safety improvement, where Human–Robot Alignment (HRA) and Task–Human Alignment (THA) exert stronger effects on bilateral safety perception than Task–Robot Alignment (TRA), underscoring the centrality of human factors at the current stage of HRC development. Moreover, this study identifies a sequential cognitive–behavioral path from safety perception to safety intention and safety behavior performance, explaining how alignment enhances safety performance. Standardized HRC guidelines further strengthen HRA, facilitating safer and more efficient collaboration. This study extends Task–Technology Fit theory to a triadic human–task–robot context and advances the concept of bilateral safety, providing theoretical and managerial guidance for developing next-generation safe collaboration systems in construction. Full article

Ras gene mutations are frequently observed in many types of cancers. However, there are currently no effective anticancer drugs against Ras-induced cancers. Therefore, identifying the downstream effectors of the Ras signaling pathway can facilitate the development of promising novel therapeutic approaches. We previously showed that oncogenic Ras induces the expression of the receptor tyrosine kinase c-Mer proto-oncogene tyrosine kinase (MerTK) in an interleukin-1 family member NF-HEV/IL-33-dependent manner and that IL-33 and MerTK contribute to oncogenic Ras-induced cell migration. In the present study, we purified the MerTK complex from NIH-3T3 cells transformed by the expression of oncogenic Ras, H-Ras (G12V). Mass spectrometric analysis identified STK38 (also known as NDR1) as a candidate binding partner for MerTK. STK38 is a serine/threonine protein kinase that plays diverse roles in normal and cancerous cells. In addition to MerTK knockdown, STK38 knockdown effectively attenuated the H-Ras (G12V)-induced migration of NIH-3T3 cells. STK38 kinase activity is required for oncogenic Ras-induced cell migration and MerTK tyrosine phosphorylation. Furthermore, MerTK or STK38 knockdown attenuated the activation of Rac1 and Cdc42. Taken together, these results revealed a novel role for STK38 in oncogenic Ras-induced enhanced cell migration, which may be useful for developing novel therapeutic strategies targeting Ras-mutated cells. Full article

Heavy metal(loid) (HM) contamination in water arises from various anthropogenic activities and natural processes, posing risks to human health through ingestion and dermal absorption. Although numerous studies have assessed health risks associated with HMs in water, inconsistencies in the selection of exposure and toxicity factors limit comparability and reliability across studies. To address this gap, the aim of this review was to provide a comprehensive synthesis of exposure and toxicity factors used in health risk assessment (HRA) of HMs in water. The objectives were to evaluate the variability in ingestion, body weight, exposure duration and frequency, and dermal contact parameters, as well as in reference doses and cancer slope factors and to propose standardized values and statistical distributions for more consistent risk estimation. A systematic search of the Scopus database retrieved 806 studies, from which highly cited articles (≥100 citations) and recent publications (2023–2025) were prioritized for analysis. The findings revealed substantial variability in factors and showed that probabilistic approaches, particularly Monte Carlo simulation, were increasingly applied and provided more reliable estimates than traditional deterministic methods. The highest agreement was observed for exposure frequency for ingestion (365 days/year) and skin surface area (18,000 cm²), each applied in 75.5% of cases. By identifying inconsistencies in current practices and proposing standardized exposure and toxicity values and distributions for water, this review is expected to offer practical recommendations to improve the robustness, reliability, and comparability of HRAs, ultimately informing more effective policy-making and water management practices. Full article

Human activities have accelerated the extinction of species, driving biodiversity loss and ecosystem degradation. Establishing protected areas (PAs) that encompass habitats of endangered species is essential for achieving biodiversity conservation and ecosystem protection goals. This study aimed to identify and prioritize critical conservation areas for the endangered long-tailed goral (Naemorhedus caudatus) in five regions of Gangwon and Gyeongbuk Provinces, South Korea. The MaxEnt model was applied to predict the potential habitat of the species, considering key environmental factors such as topographic, distance-related, vegetation, and land cover variables. The InVEST Habitat Risk Assessment (HRA) model was used to quantitatively assess cumulative risks within the habitat from the impacts of forest development and anthropogenic pressures. Subsequently, the Zonation software was employed for spatial prioritization by integrating the outputs of the models, and core conservation areas (CCAs) with high ecological value were identified through overlap analysis with 1st-grade areas from the Ecological and Nature Map (ENM). Results indicated that suitable habitats for the long-tailed goral were mainly located in forested regions, and areas subjected to multiple stressors faced elevated habitat risk. High-priority areas (HPAs) were primarily forested zones with high habitat suitability. The overlap analysis emphasized the need to implement conservation measures targeting CCAs while also managing additional HPAs outside CCAs, which are not designated as ENM. This study provides a methodological framework and baseline data to support systematic conservation planning for the long-tailed goral, offering practical guidance for future research and policy development. Full article