Search Results (409)

Cancer has remained one of the leading causes of death worldwide throughout history despite significant advancements in drug development, radiation therapy, and surgery. Traditional chemotherapeutic small molecules are often hindered by narrow therapeutic indices and limited specificity, leading to suboptimal clinical outcomes. On the other hand, more advanced approaches, such as antibody–drug conjugates (ADCs), frequently encounter obstacles, including poor tumor penetration and prohibitive production costs. The tumor-forming and metastatic capacity of cancer further challenges currently available cancer therapies by creating a biochemical milieu known as the tumor microenvironment (TME). Although solid tumor development presents significant obstacles, it also opens new avenues for innovative therapeutic approaches. It is well-documented that as tumors grow beyond 1–2 mm³ in size, they undergo profound changes in their microenvironment, including alterations in oxygen levels, pH, enzymatic activity, surface antigen expression, and the cellular composition of the stroma. These changes create unique opportunities that can be exploited to develop novel and innovative therapeutics. Currently, numerous ADCs, small-molecule–drug conjugates (SMDCs), and prodrugs are being developed to target specific aspects of these microenvironmental changes. In this review, we explore five TME parameters in detail, with a focus on their relevance to specific cancer types, phenotypic identifiers, and preferred methods of therapeutic targeting. Additionally, we examine the chemical moieties available to target these changes, providing a framework for design strategies that exploit the dynamics of the tumor microenvironment. Full article

Downhole kick is one of the most severe safety hazards in deep and ultra-deep well drilling operations. Traditional monitoring methods, which rely on surface flow rate and fluid level changes, are limited by their delayed response and insufficient sensitivity, making them inadequate for early warning. This study proposes a real-time monitoring technique for gas content in drilling fluid based on the attenuation principle of Ba-133 γ-rays. By integrating laboratory static/dynamic experiments and Geant4-11.2 Monte Carlo simulations, the influence mechanism of gas–liquid two-phase media on γ-ray transmission characteristics is systematically elucidated. Firstly, through a comparative analysis of radioactive source parameters such as Am-241 and Cs-137, Ba-133 (main peak at 356 keV, half-life of 10.6 years) is identified as the optimal downhole nuclear measurement source based on a comparative analysis of penetration capability, detection efficiency, and regulatory compliance. Compared to alternative sources, Ba-133 provides an optimal energy range for detecting drilling fluid density variations, while also meeting exemption activity limits (1 × 10⁶ Bq) for field deployment. Subsequently, an experimental setup with drilling fluids of varying densities (1.2–1.8 g/cm³) is constructed to quantify the inverse square attenuation relationship between source-to-detector distance and counting rate, and to acquire counting data over the full gas content range (0–100%). The Monte Carlo simulation results exhibit a mean relative error of 5.01% compared to the experimental data, validating the physical correctness of the model. On this basis, a nonlinear inversion model coupling a first-order density term with a cubic gas content term is proposed, achieving a mean absolute percentage error of 2.3% across the full range and R² = 0.999. Geant4-based simulation validation demonstrates that this technique can achieve a measurement accuracy of ±2.5% for gas content within the range of 0–100% (at a 95% confidence interval). The anticipated field accuracy of ±5% is estimated by accounting for additional uncertainties due to temperature effects, vibration, and mud composition variations under downhole conditions, significantly outperforming current surface monitoring methods. This enables the high-frequency, high-precision early detection of kick events during the shut-in period. The present study provides both theoretical and technical support for the engineering application of nuclear measurement techniques in well control safety. Full article

Using lightweight concrete (LWC) reduces the dead weight of the concrete structure by 25–30% compared to ordinary concrete. However, harmful and corrosive substances penetrate the lightweight concrete matrix due to its high permeability, resulting in higher maintenance costs and a reduced structure service life. Therefore, in harsh environments where conventional steel bars are susceptible to corrosion, fibre-reinforced polymer (FRP) bars should be used for reinforcement. However, there is a paucity of experimental studies regarding LWC structural elements reinforced with FRP bars. Shear strength is a critical limit state that typically determines the proper design of such elements, ensuring the required safety margin and an appropriate level of reliability. The research work was conducted to compare the experimentally determined shear strengths (V_exp) of 50 structural elements (beams, slabs) made of LWC/FRP with code predictions (V_code) made according to eight codes used for design. Based on this comparison, the so-called conformity coefficient (V_exp/V_code) was calculated and used to assess which provision documents are the best, considering the entire population of test results. The work demonstrated that the recent Eurocode best predicts the shear strength of LWC/FRP elements. Full article

Objectives: Sialic acid (SA), a naturally occurring compound abundantly found in birds’ nests, holds immense promise for skincare applications owing to its remarkable biological properties. However, its low bioavailability, poor stability, and limited skin permeability have constrained its widespread application. Methods: To overcome these challenges, SA was encapsulated within nanoliposomes (NLPs) by the high-pressure homogenization technique to develop an advanced and efficient transdermal drug delivery system. The skincare capabilities of this novel system were comprehensively evaluated across multiple experimental platforms, including in vitro cell assays, 3D skin models, in vivo zebrafish studies, and clinical human trials. Results: The SA-loaded NLPs (SA-NLPs) substantially improved the transdermal penetration and retention of SA, facilitating enhanced cellular uptake and cell proliferation. Compared to free SA, SA-NLPs demonstrated a 246.98% increase in skin retention and 1.8-fold greater cellular uptake in HDF cells. Moreover, SA-NLPs protected cells from oxidative stress-induced damage, stimulated collagen synthesis, and effectively suppressed the secretion of matrix metalloproteinases, tyrosinase activity, and melanin production. Additionally, zebrafish-based assays provided in vivo evidence of the skincare efficacy of SA-NLPs. Notably, clinical evaluations demonstrated that a 56-day application of the SA-NLPs-containing cream resulted in a 4.20% increase in L*, 7.87% decrease in b*, 8.45% decrease in TEWL, and 4.01% reduction in wrinkle length, indicating its superior brightening, barrier-repair, and anti-aging effects. Conclusions: This multi-level, systematic investigation strongly suggests that SA-NLPs represent a highly promising transdermal delivery strategy, capable of significantly enhancing the anti-aging, barrier-repair, and skin-brightening properties of SA, thus opening new avenues for its application in the fields of dermatology and cosmeceuticals. Full article

Background/Objectives. Chronic inflammatory skin disorders, such as atopic dermatitis and psoriasis, require safe and effective topical treatments. This study aimed to develop and evaluate a novel anti-inflammatory emulsion enriched with menthol, capsaicin, amino acids (glycine, arginine, histidine), and boswellic acid. Methods. Three formulations were prepared: a control (E1), a partial (E2), and a comprehensive formulation (E3). Physicochemical analyses included texture profiling, rheological behavior, pH stability, moisture content, and particle size distribution. Results. E3 demonstrated superior colloidal stability, optimal pH (5.75–6.25), and homogenous droplet size (<1 µm), indicating favorable dermal delivery potential. Ex vivo permeation studies revealed effective skin penetration of menthol and amino acids, with boswellic acid remaining primarily in the epidermis, suggesting localized action. Under oxidative stress conditions, E3 significantly improved fibroblast viability, indicating synergistic cytoprotective effects of combined active ingredients. While individual compounds showed limited or dose-dependent efficacy, their combination restored cell viability to near-control levels. Conclusions. These findings support the potential of this multi-component emulsion as a promising candidate for the topical management of inflammatory skin conditions. Full article

With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood–brain barrier (BBB), such as Cryptococcus neoformans. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis. Full article

Urban regeneration, as a key strategy for promoting sustainable development of urban areas, requires innovative digital technologies to address increasingly complex urban challenges in its implementation. With the fast advancement of digital technologies such as artificial intelligence (AI), Internet of Things (IoT), and big data, these technologies have extensively penetrated various dimensions of urban regeneration, from planning and design to implementation and post-operation management, providing new possibilities for improving urban regeneration efficiency and quality. However, the existing literature lacks a systematic evaluation of technology application patterns across different project scales and phases, comprehensive analysis of stakeholder–technology interactions, and quantitative assessment of technology distribution throughout the urban regeneration lifecycle. This research gap limits the in-depth understanding of how digital technologies can better support urban regeneration practices. This study aims to identify and quantify digital technology application patterns across urban regeneration stages, scales, and stakeholder configurations through systematic analysis of 56 high-quality articles from the Scopus and Web of Science databases. Using a mixed-methods approach combining a systematic literature review, bibliometric analysis, and meta-analysis, we categorized seven major digital technology types and analyzed their distribution patterns. Key findings reveal distinct temporal patterns: GIS and BIM/CIM technologies dominate in the pre-urban regeneration (Pre-UR) stage (10% and 12% application proportions, respectively). GIS applications increase significantly to 14% in post-urban regeneration (Post-UR) stage, while AI technology remains underutilized across all phases (2% in Pre-UR, decreasing to 1% in Post-UR). Meta-analysis reveals scale-dependent technology adoption patterns, with different technologies showing varying effectiveness at building-level, district-level, and city-level implementations. Research challenges include stakeholder digital divides, scale-dependent adoption barriers, and phase-specific implementation gaps. This study constructs a multi-dimensional analytical framework for digital technology support in urban regeneration, providing quantitative evidence for optimizing technology selection strategies. The framework offers practical guidance for policymakers and practitioners in developing context-appropriate digital technology deployment strategies for urban regeneration projects. Full article

The natural history of focal non-infected lesions of the abdominal aorta (fl-AA) remains unclear and largely depends on their aetiology. These lesions often involve a focal “tear” or partial disruption of the arterial wall. Penetrating aortic ulcers (PAUs) and intramural hematomas (IMHs) are examples of focal tears in the aortic wall that can either progress to dilatation (saccular aneurysm) or fail to fully propagate through the medial layers, potentially leading to aortic dissection. These conditions typically exhibit a morphology consistent with eccentric saccular aneurysms. The management of focal non-infected pathologies of the abdominal aorta remains a subject of debate. Unlike fusiform abdominal aortic aneurysms, the inconsistent definitions and limited information regarding the natural history of saccular aneurysms (sa-AAAs) have prevented the establishment of universally accepted practice guidelines for their management. As emphasized in the latest 2024 ESVS guidelines, the focal nature of these diseases makes them ideal candidates for endovascular repair (class of evidence IIa—level C). Moreover, the Society for Vascular Surgery just referred to aneurysm diameter as an indication for treatment suggesting using a smaller diameter compared to fusiform aneurysms. Consequently, the management of saccular aneurysms is likely heterogeneous amongst different centres and different operators. Endovascular repair using tube stent grafts offers benefits like reduced recovery times but carries risks of migration and endoleak due to graft rigidity. These complications can influence long-term success. In this context, the use of endovascular bifurcated grafts may provide a more effective solution for treating these focal aortic pathologies. It is essential to achieve optimal sealing regions through anatomical studies of aortic morphology. Additionally, understanding the anatomical characteristics of focal lesions in challenging necks or para-visceral locations is indeed crucial in device choice. Off-the-shelf devices are favoured for their time and cost efficiency, but new endovascular technologies like fenestrated endovascular aneurysm repair (FEVAR) and custom-made devices enhance treatment success and patient safety. These innovations provide stent grafts in various lengths and diameters, accommodating different aortic anatomies and reducing the risk of type III endoleaks. Although complicated PAUs and focal saccular aneurysms rarely arise in the para-visceral aorta, the consequences of rupture in this segment might be extremely severe. Experience borrowed from complex abdominal and thoracoabdominal aneurysm repair demonstrates that fenestrated and branched devices can be deployed safely when anatomical criteria are respected. Elective patients derive the greatest benefit from a fenestrated graft, while urgent cases can be treated confidently with off-the-shelf multibranch systems, reserving other types of repairs for emergent or bail-out cases. While early outcomes of these interventions are promising, it is crucial to acknowledge that limited aortic coverage can still impede effective symptom relief and lead to complications such as aneurysm expansion or rupture. Therefore, further long-term studies are essential to consolidate the technical results and evaluate the durability of various graft options. Full article

Optical coherence tomography (OCT) is a non-invasive imaging technique that provides high-resolution, real-time visualization of soft and hard periodontal tissues. It offers micrometer-level resolution (typically ~10–15 μm) and a scan depth ranging from approximately 0.5 to 2 mm, depending on tissue type and system configuration. The field of view generally spans a few millimeters, which is sufficient for imaging gingiva, sulcus, and superficial bone contours. Over the past two decades, its application in periodontology has gained increasing attention due to its ability to detect structural changes in gingival and alveolar tissues without the need for ionizing radiation. Various OCT modalities, including time-domain, Fourier-domain, and swept-source OCT, have been explored for periodontal assessment, offering valuable insights into tissue morphology, disease progression, and treatment outcomes. Recent innovations include the development of three-dimensional (3D) OCT imaging and OCT angiography (OCTA), enabling the volumetric visualization of periodontal structures and microvascular patterns in vivo. Compared to conventional imaging techniques, such as radiography and cone beam computed tomography (CBCT), OCT offers superior soft tissue contrast and the potential for dynamic in vivo monitoring of periodontal conditions. Recent advancements, including the integration of artificial intelligence (AI) and the development of portable OCT systems, have further expanded its diagnostic capabilities. However, challenges, such as limited penetration depth, high costs, and the need for standardized clinical protocols, must be addressed before widespread clinical implementation. This narrative review provides an updated overview of the principles, applications, and technological advancements of OCT in periodontology. The current limitations and future perspectives of this technology are also discussed, with a focus on its potential role in improving periodontal diagnostics and personalized treatment approaches. Full article

Background/Objectives: The treatment of atopic dermatitis frequently involves using a topical corticosteroid and a moisturizer. While the sequential application of these products is a common dermatological practice, their influence on drug penetration remains poorly understood. There is no clear evidence on how hydration, application sequence, and massage affect cutaneous drug delivery. Hence, this study aimed to evaluate the effects of formulation type, moisturizer composition, application sequence, and mechanical stimulation on betamethasone dipropionate (BET) cutaneous penetration. Methods: Two commercial formulations (cream and ointment) of BET were evaluated in different experimental conditions, including drug application combined with moisturizers (Cetaphil^®, as an emollient; Nivea^®, as an occlusive) pre- or post-application, with or without a 30 s massage. In vitro skin penetration assays were conducted for 12 h using porcine skin mounted in modified Franz diffusion cells. BET levels were extracted from the skin layers and quantified by HPLC. Results: The cutaneous BET penetration was strongly influenced by the application sequence, type of moisturizer, and mechanical stimuli. Pre-application of an occlusive or emollient moisturizer, followed by 30 s physical stimuli, significantly enhanced drug retention in the stratum corneum. For the cream, pre-application of moisturizers followed by massage notably increased BET levels in both the stratum corneum and viable skin. Conversely, post-application of moisturizers hindered BET absorption. The ointment showed limited penetration across all conditions, with no drug detected in the viable skin. Conclusions: The results showed pre-hydrating the skin, combined with a 30 s massage, was the best strategy for BET diffusion into the skin following cream administration. The formulation type and the order of application directly influence the effectiveness of drug therapy and the topical absorption of BET. Full article

Background/Objectives: Pediatric asthma is a leading cause of emergency department visits, and air pollution is a known primary environmental trigger. Although worldwide air pollutants have been associated with asthma exacerbations, limited data have been reported in the Eastern Province of Saudi Arabia. This study aimed to investigate the relationship between air pollution and pediatric asthma admissions among children aged 2 to 14 years old at King Fahd Hospital of the University Hospital (KFHU). Methods: This is a retrospective cohort study, over 366 days, including 1750 pediatric asthma-related ER visits and daily concentrations of air pollutants (PM_2.5, PM₁₀, NO₂, SO₂, CO, and O₃) and meteorological factors (temperature and humidity). Various statistical models, such as Poisson regression and ARIMA, were applied to determine the association between pollutants levels and hospital ER visits. The data were visit-based in nature, and it was not possible to follow up with repeat visits or for admission status for individual patients. Results: Elevated levels of PM_2.5, NO₂, and CO were significantly associated with more pediatric asthma ER visits, mainly on the same day and with short lags. PM_2.5 displayed the strongest association, consistent with its deeper pulmonary penetration and greater toxicity. Also, PM₁₀ levels were inversely associated with ER visits, possibly due to particle size and deposition location differences. Significantly correlated with increased ER visits are lower ambient temperature and higher humidity. Conclusions: This study offers strong evidence on the relationship between air pollution and pediatric asthma events, in turn highlighting the vital importance of air quality regulation, public health policies, and clinical vigilance for environmental exposures. Full article

HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically regulates RNA polymerase II processivity to alter viral transcription states. Recent studies reveal its context-dependent variability: while Tat recruits chromatin modifiers and scaffolds non-coding RNAs to stabilize epigenetic silencing in latently infected cells, it also triggers rapid transcriptional amplification upon cellular activation. This review systematically analyzes the bistable regulatory mechanism of Tat and investigates advanced technologies for reprogramming this switch to eliminateviral reservoirs and achieve functional cures. Conventional approaches targeting Tat are limited by compensatory viral evolution and poor bioavailability. Next-generation interventions will employ precision-engineered tools, such as AI-optimized small molecules blocking Tat-P-TEFb interfaces and CRISPR-dCas9/Tat chimeric systems, for locus-specific LTR silencing or reactivation (“block and lock” or “shock and kill”). Advanced delivery platforms, including brain-penetrant lipid nanoparticles (LNPs), enable the targeted delivery of Tat-editing mRNA or base editors to microglial reservoirs. Single-cell multiomics elucidates Tat-mediated clonal heterogeneity, identifying “switchable” subpopulations for timed interventions. By integrating systems-level Tat interactomics, epigenetic engineering, and spatiotemporally controlled delivery, this review proposes a roadmap to disrupt HIV-1 persistence by hijacking the Tat switch, ultimately bridging mechanistic insights to clinical applications. Full article

Background: Cancer vaccines represent a groundbreaking advancement in cancer immunotherapy, utilizing tumor antigens to induce tumor-specific immune responses. However, challenges like tumor-induced immune resistance and technical barriers limit the widespread application of predefined antigen vaccines. Here, we investigated the potential of viral protein R (Vpr) peptides as effective candidates for constructing anonymous antigen vaccines in situ by directly injecting at the tumor site and releasing whole-tumor antigens, inducing robust anti-tumor immune responses to overcome the limitations of predefined antigen vaccines. Methods: The cytotoxic effects of Vpr peptides were evaluated using the CCK8 reagent kit. Membrane penetration ability of Vpr peptides was observed using a confocal laser scanning microscope and quantitatively analyzed using flow cytometry. EGFR levels in the cell culture supernatants of cells treated with Vpr peptides were evaluated using an ELISA. Surface exposure of CRT on the tumor cell surface was observed using a confocal laser scanning microscope and quantitatively analyzed using flow cytometry. The secretion levels of ATP from tumor cells were evaluated using an ATP assay kit. HMGB1 release was evaluated using an ELISA. Mouse (Male C57BL/6 mice aged 4 weeks) MC38 and LLC bilateral subcutaneous tumor models were established to evaluate the therapeutic effects of Vpr peptides through in situ vaccination. Proteomic analysis was performed to explore the mechanism of anti-tumor activity of Vpr peptides. Results: Four Vpr peptides were designed and synthesized, with P1 and P4 exhibiting cytotoxic effects on tumor cells, inducing apoptosis and immunogenic cell death. In mouse tumor models, in situ vaccination with Vpr peptide significantly inhibited tumor growth and activated various immune cells. High-dose P1 monotherapy demonstrated potent anti-tumor effects, activating DCs, T cells, and macrophages. Combining ISV of P1 with a CD47 inhibitor SIRPαFc fusion protein showed potent distant tumor suppression effects. Proteomic analysis suggested that Vpr peptides exerted anti-tumor effects by disrupting tumor cell morphology, movement, and adhesion, and promoting immune cell infiltration. Conclusions: The designed Vpr peptides show promise as candidates for in situ vaccination, with significant anti-tumor effects, immune activation, and favorable safety profiles observed in mouse models. In situ vaccination with Vpr-derived peptides represents a potential approach for cancer immunotherapy. Full article

The secondary lining of a tunnel is a critical load-bearing component, whose stability and structural integrity are essential for ensuring the overall safety of the tunnel. However, identifying lining structures and estimating their thickness using ground-penetrating radar (GPR) remain challenging due to several inherent limitations. First, the limited electromagnetic contrast between the primary and secondary linings results in weak interface reflections in GPR imagery, thereby hindering accurate delineation. Second, construction errors such as over-excavation or under-excavation often lead to complex interface geometries, further complicating the interpretation of GPR signals. To address these challenges, we propose an enhanced YOLOv8-seg network capable of performing pixel-level segmentation on GPR images to accurately delineate secondary lining regions and estimate their thickness. The model integrates a convolutional block attention module (CBAM) to refine feature extraction by emphasizing critical characteristics of the two interface layers through channel-wise and spatial attention mechanisms. The model is first pretrained on the COCO dataset and subsequently fine-tuned via transfer learning using a hybrid GPR dataset comprising real-world measurements and numerically simulated data based on forward modeling. Finally, the model is validated on real-world GPR measurements acquired from the Longhai tunnel. Experimental results demonstrate that the proposed method reliably identifies secondary tunnel linings and accurately estimates their average thickness. Full article

Glioblastoma is the most prevalent and aggressive form of brain malignancy. Actual treatments face several challenges due to its high aggressiveness and poor prognosis. The chemotherapeutic agent temozolomide (TMZ) has limited therapeutic efficacy, and mutations in the tumour protein p53 gene (TP53) have been associated with treatment resistance. Thus, this study aimed to explore an innovative therapeutic strategy to enhance treatment efficacy of GBM. Previously, our team had developed a WRAP5 cell-penetrating peptide (CPP) functionalized with a transferrin receptor ligand (Tf) for the targeted delivery of TMZ and a p53-encoding plasmid to glioma cells. Our research had elucidated the circadian oscillations of the clock genes in the U87 glioma cells by employing two different computational models and observed that T16 and T8 time points revealed the highest circadian activity for Bmal1 and Per2 genes, respectively. Similar analysis was conducted for the transferrin receptor, which revealed that T7 and T8 were the key time points for its expression. A confocal microscopy study indicated the highest intracellular uptake of complexes and p53 mRNA expression at T8, the time point with the highest Per2 and transferrin receptor expression. Following mRNA analysis, the evaluation of p53 levels confirmed transcriptional changes at the protein level, and that T16 appears to be a favourable time point for enhancing therapeutic efficacy in U87 glioblastoma cells. These findings suggested that synchronizing the complexes’ administration with the biological clock of GBM cells may significantly improve glioblastoma therapeutics. Full article