Search Results (210)

Background/Objectives: Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, driven by invasive behavior and frequent resistance to systemic therapies. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) benefit patients with EGFR-mutant NSCLC, but their efficacy is often limited by tumor-intrinsic and environmental resistance mechanisms. Benzo[a]pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon from tobacco smoke, combustion, and dietary sources, is a known carcinogen; however, its role in modulating therapeutic responses is poorly understood. Studies, including ours, implicate the platelet-activating factor-receptor (PAFR) pathway in mediating environmental pollutant and therapy-induced effects on tumor growth and microvesicle particle (MVP) release. We hypothesized that PAFR activation mediates BaP-induced NSCLC progression and influences EGFR-TKI responses. Methods: We assessed the effects of BaP, PAFR agonist CPAF, EGFR-TKIs, and their combinations on cell viability, proliferation, migration, anchorage-independent growth, and MVP secretion. Results: BaP did not alter cell survival but significantly increased migration, growth, colony formation, and MVP release, similar to CPAF, and these effects were blocked by a PAFR antagonist or acid sphingomyelinase inhibitor. Notably, BaP did not significantly reduce EGFR-TKI efficacy at tested concentrations. Conclusions: These results show that environmental carcinogens modulate NSCLC behavior through PAFR signaling without compromising EGFR-TKI responsiveness, highlighting PAFR as a potential therapeutic target. Full article

The containment structure serves as the final leak-tight barrier of nuclear power plants, making it critical to nuclear safety. The stable performance of the steel liner anchorage system is the fundamental prerequisite for maintaining the structural integrity of the containment. However, existing studies lack systematic quantification of the mechanical behavior and bearing capacity contributions of key components (angle steels, studs) in such anchorage system, creating significant uncertainties to the engineering design of steel liner plates. In this study, a high-fidelity three-dimensional numerical model of the steel liner composite anchorage system is established. A systematic parametric analysis is conducted to investigate the influence of angle steel quantity and stud row number on the system’s mechanical response. Three typical failure modes are identified for the steel liner anchorage system, and the individual contributions of long angle steels, short angle steels and studs to the global load-bearing capacity are quantified independently. The rationality of the angle steel spacing design employed in the prototype structure is confirmed, and the nonlinear contribution characteristics of angle steels and studs are elucidated. The findings provide a crucial theoretical foundation for the optimal design and safety assessment of the steel liner anchorage system in nuclear plants. Full article

Breast cancer treatment remains challenging due to therapeutic resistance and the limited availability of effective molecular targets. We investigated the anticancer effects of sulforaphane (SFN) and broccoli sprout extract (BSE), an SFN-enriched phytochemical formulation, in MCF7 and MDA-MB-231 breast cancer cells. Cell viability, colony formation, and apoptotic responses were evaluated using standard in vitro assays, and underlying mechanisms were examined by flow cytometry and Western blot analysis. BSE and SFN reduced cell viability in a dose-dependent manner, suppressed anchorage-independent growth, and induced apoptosis associated with increased reactive oxygen species (ROS) generation and activation of c-Jun N-terminal kinase and p38 MAPK signaling pathways. These effects were accompanied by mitochondrial depolarization, G2/M cell cycle arrest, and caspase activation. Pharmacokinetic analysis in rats demonstrated that oral administration of BSE resulted in sustained, dose-dependent systemic exposure to SFN. Consistent with these findings, oral BSE significantly inhibited tumor growth in breast cancer xenograft models. Collectively, these results indicate that BSE exerts anticancer effects through coordinated modulation of ROS-associated MAPK signaling, mitochondrial dysfunction, and apoptotic pathways, and may serve as a promising orally administered SFN-containing phytochemical formulation that may function as a delivery matrix for breast cancer management. Full article

Return-type cable suspension bridges transfer the main-cable force to the anchorage predominantly in the horizontal direction, which may induce coupled sliding–overturning instability of the anchorage–foundation system. This study examines the stability of return-type cable gravity anchorage using the composite anchorage of the Jixin Expressway Yellow River Three Gorges Bridge as the prototype. A 1:100 laboratory specimen was designed based on similarity theory and tested under incremental loading until failure. Four configurations were considered by combining two embedment ratios (1/4 and 1/2) with two base types (flat-base and shear-keyed). Horizontal displacement, overturning angle, interface contact stress, and foundation strain were monitored throughout loading. Because the return-type cable transmits a predominantly horizontal force, the anchorage–foundation contact stress exhibits pronounced asymmetry between the toe and heel regions, and this stress asymmetry governs the coupled sliding–overturning instability mode. The shallow flat-base case exhibited a distinct displacement and contact stress jump at high load levels, followed by rapid rotation, indicating slip–tilt coupled instability. Increasing embedment improved confinement and delayed the onset of nonlinear deformation, but the flat-base configuration still showed pronounced toe stress concentration. By contrast, the shear-keyed base mobilized cooperative bearing of the surrounding foundation, producing smoother stress–strain evolution and higher ultimate capacity. Moreover, the shear-keyed base mitigates the stress asymmetry at the anchorage–foundation interface, leading to a more symmetric distribution of contact pressure and improved overall stability. Three-dimensional finite-element simulations reproduced the measured trends in displacement, stress concentration near the toe, and strain development, providing independent verification. The results clarify the dominant instability mechanism of return-type cable gravity anchors and offer design implications for embedment depth and shear-keyed base detailing. Full article

Chronic exposure to benzo[a]pyrene (BaP), a Group 1 IARC carcinogen, is a major driver of lung carcinogenesis; however, how sustained subcytotoxic exposure reprograms bronchial epithelium toward preneoplastic states remains poorly defined. Here, we subjected BEAS-2B human bronchial epithelial cells to 12 weeks of continuous BaP at environmentally relevant concentrations (0.1 and 1.0 µM) and interrogated the resulting phenotypes using an integrated multi-scale framework encompassing functional toxicology, RT-qPCR, RNA-seq, phospho-kinase/NF-κB arrays, and organotypic air–liquid interface (ALI) cultures. Cells maintained metabolic competence throughout, evidenced by sustained CYP1A1 and CYP1B1 induction at both acute (4 h) and chronic (12-week) timepoints, while accumulating genotoxic stress as demonstrated by dose-dependent nuclear γ-H2AX foci formation and ATM phosphorylation (Ser1981). RNA-seq revealed a dose-dependent transcriptional shift: 0.1 µM BaP yielded 119 differentially expressed genes (DEGs; |log2FC| ≥ 1, FDR < 0.05), whereas 1.0 µM generated 255 DEGs. Downregulated transcripts were enriched for extracellular matrix and cell-adhesion programs (COL14A1, ADAMTS2, CSMD3, CADM3), while upregulated genes encompassed inflammatory, calcium-signaling, and vesicle-trafficking modules (NFATC4, CSF2RA, SYT1, PCLO). Phospho-kinase/NF-κB arrays confirmed a p53/NF-κB signaling nexus, with concurrent activation of MAPK/ERK (Thr202/Tyr204) and PI3K/Akt (Ser473) pathways. Despite persistent genotoxic stress, cells did not acquire anchorage-independent growth and remained non-tumorigenic in vivo. Critically, ALI organotypic cultures derived from BaP-exposed cells exhibited histological dysplasia, nuclear pleomorphism, and disrupted apical-basal polarity. These findings mechanistically link chronic BaP exposure to an initiation-like preneoplastic state and establish a validated 2D/3D multi-omics platform for PAH-driven lung carcinogenesis research. Full article

Constitutively active KRAS mutations are highly prevalent in lung cancers, but the direct role of its downstream phosphatidylinositol 3-kinase (PI3K) pathway in tumor progression remains unclear. A previous study established the requirement for PIK3CA, the alpha catalytic isoform, in lung tumor development in mouse models with an intact Trp53 tumor suppressor. In this study, we further investigated the requirement of PIK3CA for tumor growth both in vitro and in vivo. We first generated a “KPA” cell line by genetically deleting Pik3ca from a murine lung adenocarcinoma “KP” cell line harboring oncogenic Kras^G12D and lacking Trp53. We also examined the requirement for STK11, a tumor suppressor and metabolic regulator frequently co-mutated with KRAS in lung cancer. We found that Pik3ca is not required for cell survival and growth in vitro, even under anchorage-independent conditions, but reduced the growth rate by 15%. We next orthotopically implanted KP and KPA cells into syngeneic mice and found that PIK3CA is absolutely required for tumor progression, even in the absence of Trp53. Implantation of KP cells, or a “KPS” cell line lacking the Stk11 gene, led to rapid tumor growth and death of all host animals. In contrast, mice implanted with KPA cells all survived with no detectable lung tumors. The gene expression profiles from cultured cell lines suggest oxidative stress as a potential vulnerability of KPA cells. Indeed, we found KPA cells were more sensitive to hydrogen peroxide and diethyl maleate-induced oxidative stress as compared to KP and KPS cells. Together, these results indicate that PIK3CA is not required for lung cancer cell growth induced by mutant KRAS in vitro but is essential for in vivo progression and growth. Full article

Background/Objectives: Orthodontic mini-implants have become indispensable in modern orthodontics due to their ability to provide absolute anchorage, independent of patient compliance. Our research aims to illustrate the versatility of mini-implants in addressing diverse biomechanical challenges across different planes of tooth movement (sagittal, transverse, and vertical) based on a retrospective clinical analysis. Methods: A retrospective analysis of orthodontic treatments performed with mini-implants (Dual Top and JS systems) was conducted, focusing on predefined biomechanical objectives and outcomes. The analysis encompassed distinct biomechanical applications, including incisor retraction and space closure using sequential direct and indirect anchorage; transverse and vertical correction of adult open bite through mini-implant–assisted rapid palatal expansion (MARPE) and molar intrusion; deep bite correction via simultaneous upper and lower incisor intrusion; and unilateral molar distalization using palatal skeletal anchorage. Results: Mini-implants provided stable, reproducible anchorage in all cases, enabling complex three-dimensional tooth movements with minimal side effects. Sequential reuse of the same mini-implants for both indirect and direct anchorage reduced treatment invasiveness and enhanced anchorage efficiency. Combined skeletal expansion and posterior intrusion allowed improved transverse and vertical control in adult open-bite presentations. Pure incisor intrusion was achieved without molar extrusion or incisor proclination, while unilateral molar distalization was effectively managed using palatal skeletal anchorage. Across all cases, mini-implants enhanced treatment efficiency, reduced the need for auxiliary appliances, and ensured predictable outcomes. Conclusions: Orthodontic mini-implants represent a highly versatile and minimally invasive anchorage system adaptable to a broad range of biomechanical situations. Their ability to provide stable, reusable, and site-specific anchorage supports efficient correction of complex malocclusions and reinforces their pivotal role in contemporary orthodontic practice. Full article

Multi-walled carbon nanotubes (MWCNTs) are increasingly incorporated into industrial and consumer products, raising concerns about potential carcinogenicity because their physicochemical properties vary widely among materials. Although Mitsui-7 has been classified as possibly carcinogenic to humans (IARC, Group 2B), the carcinogenic potential of domestically manufactured MWCNTs and the determinants underlying material-specific differences remain insufficiently characterized. Here, we applied an adverse outcome pathway (AOP)-oriented integrated testing strategy (ITS) to compare four domestically manufactured MWCNTs with Mitsui-7 using human bronchial epithelial BEAS-2B cells. Acute responses were assessed by measuring cytotoxicity and intracellular reactive oxygen species (ROS). Exposure concentrations for long-term studies were selected using range-finding assays, and cells were then exposed for four weeks at non-cytotoxic concentrations. Following chronic exposure, transformation-related phenotypes were evaluated using anchorage-independent growth, anchorage-dependent clonogenicity, wound healing migration, and Transwell–Matrigel invasion assays, and tumorigenic potential was examined in xenograft models using colony-derived cells. Highly aggregated MWCNTs elicited stronger oxidative stress and were associated with increased proliferation/clonal expansion, enhanced anchorage-independent colony formation, and increased tumor formation in vivo, whereas other materials showed more limited or endpoint-specific responses. Overall, the results indicate that MWCNT-associated carcinogenic potential is material-dependent rather than a uniform class effect and support the utility of an AOP-aligned ITS for nanosafety assessment and hazard differentiation of carbon-based nanomaterials. Full article

Prolyl 3-hydroxylase 2 (P3H2) is a key enzyme involved in the architecture of the extracellular matrix (ECM). While previously shown to be regulated by VEGF-A and to play a role in angiogenesis, its function in cancer remains ambiguous. While characterized as a tumor suppressor, its precise function in colorectal cancer (CRC) progression is poorly defined. Bioinformatic analysis and patient data reveal that P3H2 transcript levels are significantly reduced in colon adenocarcinoma tissues, showing a progressive decline in metastatic lesions. Furthermore, VEGF-A exposure upregulates P3H2 transcripts in the HCT116 CRC cell line. To investigate its impact in CRC, we generated a stable HCT116 clone overexpressing P3H2. In vitro studies demonstrated that while P3H2 overexpression inhibited anchorage-independent growth, it significantly enhanced cellular invasion without altering cell proliferation. In vivo, however, P3H2-overexpressing tumors exhibited accelerated tumor growth and a statistically significant increase in lung metastases. P3H2 overexpression remodeled the tumor microenvironment (TME) by modifying its main substrate, Collagen IV, resulting in the induction of increased vessels density. Our study repositions P3H2 as a dynamic enzymatic switch within the TME. This work identifies P3H2-driven ECM remodeling as a promising therapeutic axis in advanced CRC, with particular relevance for combination strategies targeting angiogenesis. Full article

SATB2 (special AT-rich binding protein 2) functions as a chromatin-associated epigenetic regulator that modulates gene expression, in part by serving as a transcriptional cofactor. This study assessed whether SATB2 overexpression is sufficient to promote in vitro transformation of human mesothelial cells and whether SATB2 suppression in mesothelioma cancer stem cell (CSC)–enriched populations is associated with altered chemoresistance. SATB2 expression was high in human malignant pleural mesothelioma (MPM) cell lines but absent in Met5A mesothelial cells. Ectopic SATB2 expression in Met5A cells was associated with acquisition of malignant and stem cell–like phenotypes, including increased expression of stem cell markers and pluripotency-associated factors, as well as anchorage-independent growth in soft agar and spheroid formation in suspension culture. In contrast, Met5A cells transduced with an empty vector did not form colonies or mesospheres. SATB2 overexpression in Met5A cells was also associated with increased motility, migration, and invasion, accompanied by induction of epithelial–mesenchymal transition (EMT)–related transcription factors relative to empty vector controls. Conversely, shRNA-mediated SATB2 knockdown in an MPM cell line attenuated proliferation, EMT-associated features, and CSC-like characteristics. Chromatin immunoprecipitation assays identified SATB2 occupancy at promoter regions of Bcl2, XIAP, KLF4, c-Myc, NANOG, and SOX2, consistent with a role in transcriptional regulation of genes linked to transformation, pluripotency, cell survival, proliferation, and EMT. In CSC-enriched cells, SATB2 inhibition was associated with increased sensitivity to cisplatin and pemetrexed, concomitant with reduced OCT4 and SOX2 expression. Collectively, these findings support SATB2 as a candidate therapeutic target in MPM and suggest that SATB2 suppression may enhance chemotherapy response when combined with standard agents. Full article

The use of miniscrews as Temporary Skeletal Anchorage Devices (TSAD) in orthodontics has allowed clinicians to perform challenging tooth movements by dissipating undesired forces into the bone structure; thus, avoiding unwanted movement of the adjacent teeth. It is essential for miniscrews to be highly resistant to fracture during clinical use. While many studies have analysed torsional loads, none have measured the changes in flexural and bending strength of miniscrews before and after an ageing process. This study aims to analyse the resistance to orthogonal forces of miniscrews with different diameters, focusing on both new and aged materials, the latter subjected to thermocycling and autoclaving laboratory processes to simulate a 3- and a 6-month exposure to the oral environment. A total of 105 pristine miniscrews have been tested; specimens were divided into seven groups based on the different endosseous body diameters. Each group was further subdivided into three subgroups, according to the simulated ageing of the miniscrews (intact, 3 months of ageing and 6 months of ageing, respectively). An Instron Universal Testing Machine has been used to measure deflection at 0.1 mm and 0.2 mm, as well as maximum load at fracture. The results evidenced that miniscrews respond differently to cutting forces; in particular, the resistance to orthogonal loads increases as the diameter of the miniscrews increases. Linear regression analysis revealed a significant influence between all the dependent variables—maximum load, 0.1 mm deflection load, and 0.2 mm deflection load—and the independent variables, such as diameter and thermocycling (p < 0.05). Both new and aged miniscrews are suitable for orthodontic and orthopaedic loads; moreover, ageing up to 6 months does not seem to significantly decrease the resistance to shear forces for the same diameter. Linear regression analysis of the miniscrews subjected to experimental ageing showed a slight but significant decrease in resistance to orthogonal loading. Full article

Epithelial, endothelial, and many connective tissue cells are normally attached to the extracellular matrix (ECM). These cells rely on the ECM for structural support, signaling, and regulation of their behavior. When these cells lose this attachment or are in an inappropriate location, these cells soon die by a mechanism called anoikis (homelessness). Anoikis is a programmed cell death of an apoptotic nature; however, it can, in certain cases, be overcome, and detached cells can survive in the absence of the correct signals from the ECM. This is the case of malignant cells, where anoikis resistance is a prerequisite for invasion and metastasis. Without anoikis resistance (anchorage-independency), tumors would be unable to abandon their normal sites and would invade neighboring tissues and metastasize at distant locations. Anoikis is the natural barrier against cancer progression. Therefore, overcoming anoikis is a major step in cellular transformation. Cancer cells have developed many successful strategies to bypass anoikis. The main mechanism, albeit not the only one, involves hyper-activating survival pathways and over-expressing anti-apoptotic molecules. There is a strong and intertwining association between epithelial–mesenchymal transition and anoikis resistance that is discussed in depth. A better understanding of these anoikis resistance mechanisms has led to the research and development of pharmaceuticals that can counteract them. Full article

High-grade serous ovarian carcinoma (HGSC) is predominantly diagnosed at advanced stages with extensive peritoneal metastasis. A pivotal early event in HGSC development is the peritoneal seeding of tumor cells originating from the fallopian tube epithelial (FTE) precursor lesions. Ovulation releases follicular fluid (FF), which is known to contain oncogenic factors that promote FTE cell transformation. However, the specific mechanisms and factors within FF that drive the early metastatic seeding of precancerous FTE cells remain poorly defined. We investigated the role of FF in the peritoneal dissemination of FTE-derived cells, and the abundance of fibronectin (FN) as a potential key mediator. Functional assays were performed using FN-depleted FF to assess its impact on migration, invasion, anchorage-independent growth, and peritoneal attachment. The role of the fibronectin receptor, integrin β1 (ITGB1), and the signaling pathways were evaluated via knockdown studies. In vivo xenograft models were used to quantify peritoneal seeding, and mechanistic studies elucidated the involved signaling pathways. We identified FN as a critical component of FF, present at high concentrations (~210 µg/mL), that potently drives FTE cell migration, invasion, and peritoneal seeding. Depletion of FN from FF abrogated the majority of these pro-metastatic activities in vitro and led to a dramatic 82% reduction in peritoneal tumor seeding in vivo. Knockdown of ITGB1 similarly impaired seeding. Mechanistically, FF-derived FN activates the ITGB1/FAK-SRC signaling pathway to promote tumor cell motility and colonization. Our study establishes FF-fibronectin as an important regulator of the early peritoneal seeding of HGSC precursor cells. These findings reveal a direct link between ovulation and HGSC development, suggesting that targeting the FN-ITGB1 signaling axis may offer a novel preventive strategy for high-risk individuals. Full article

Ovarian cancer (OC) represents the most lethal gynecologic malignancy because the majority of patients with OC are diagnosed at advanced stages with peritoneal colonization of OC cells owing to subtle and nonspecific nature of symptoms. Thus, peritoneal colonization-directed therapeutic approaches are urgently needed for patients with advanced OC. Here, we investigated whether Ring-finger protein 126 (RNF126), an E3 ubiquitin ligase that is aberrantly upregulated in epithelial OC tissues, contributes to the peritoneal colonization of OC. RNF126-depleted OC cells showed comparable proliferation under normal culture conditions but displayed decreased growth under floating (anchorage-independent) conditions in vitro. Further analyses showed that RNF126 promoted anoikis resistance in vitro and increased peritoneal colonization in immunodeficient mice in a RING domain-dependent manner. Mechanistically, RNF126 activated the transcriptional factor NF-κB in OC cells under floating conditions in a RING domain-dependent manner, and this NF-κB activation was essential for anchorage-independent growth and peritoneal colonization of OC cells. Thus, RNF126 is a possible target for the prevention and/or therapy of peritoneally colonized OC. Full article

Temporary anchorage devices (TADs) have become integral in contemporary orthodontic biomechanics, providing reliable skeletal anchorage independent of dental support or patient compliance. This narrative review synthesizes the current evidence regarding TADs classification, design parameters, biomechanical principles, clinical insertion protocols, complication management, and technological innovations. We reviewed foundational literature and recent clinical studies with emphasis on factors affecting primary and secondary stability, including insertion torque, angulation, cortical bone characteristics, and soft-tissue considerations. Self-drilling techniques are generally preferred for maxillary sites, while pre-drilling remains indicated in dense mandibular bone to reduce thermal risk and torque overload. Clinical success is optimized when insertion torque is maintained between 5 and 10 N·cm and site-specific anatomy is respected. Reported survival rates exceed 85–95% when proper protocols are followed. While TADs are associated with relatively low complication rates, failures are usually early and linked to excessive torque, poor hygiene, or inflammation. New technologies such as cone-beam computed tomography-guided placement, 3D-printed surgical guides, and AI-based planning tools offer promising avenues for safer and more individualized treatment. In conclusion, TADs represent a predictable and versatile option for skeletal anchorage in orthodontics, provided that mechanical design, biological adaptation, and clinical handling are coherently integrated into patient-specific strategies. Full article