Search Results (6,252)

The TP53 gene, frequently mutated across multiple cancer types, plays a pivotal role in regulating the cell cycle and apoptosis through its protein, p53. Missense variants of uncertain significance (VUSs) in TP53 present challenges in understanding their impact on protein function and complicate clinical interpretation. This study aims to analyze the effects of missense VUSs in p53, as reported in the gnomAD database, with a specific focus on their impact on protein stability and phosphorylation. In this study, 33 missense VUSs in TP53 reported in the gnomAD database were analyzed using in silico tools, including PhosphositePlus v6.7.4, the Kinase Library v0.0.11, and Dynamut2. Of these analyzed variants, five disrupted known phosphorylation sites, while another five created new consensus sequences for phosphorylation. Moreover, 20 variants exhibited a moderate destabilizing effect on the protein structure. At least three missense VUSs were identified as potentially affecting p53 function, which may contribute to cancer development. These findings highlight the importance of integrating in silico structural and functional analysis to assess the pathogenic potential of missense VUSs. Full article

Background/Objectives: Neuromodulation is under investigation as a possibly effective add-on therapy in Alzheimer’s disease (AD). While transcranial pulse stimulation (TPS) has shown positive short-term effects, long-term effects have not yet been fully explored. This study aims to evaluate the long-term feasibility, safety, and potential cognitive benefits of TPS over one year in patients with Alzheimer’s disease, focusing on domains such as memory, speech, orientation, visuo-construction, and depressive symptoms. Methods: We analyzed preliminary data from the first ten out of thirty-five patients enrolled in a prospective TPS study who completed one year of follow-up and were included in a dedicated long-term database. The protocol consisted of six initial TPS sessions over two weeks, followed by monthly booster sessions delivering 6000 pulses each for twelve months. Patients underwent regular neuropsychological assessments using the Alzheimer Disease Assessment Scale (ADAS), Mini-Mental Status Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Beck Depression Inventory (BDI-II). All adverse events (AEs) were documented and monitored throughout the study. Results: Adverse events occurred in less than 1% of stimulation sessions and mainly included mild focal pain or transient unpleasant sensations, as well as some systemic behavioral or vigilance changes, particularly in patients with underlying medical conditions, with some potentially related to the device’s stimulation as adverse device reactions (ADRs). Cognitive test results showed significant improvement after the initial stimulation cycle (ADAS total improved significantly after the first stimulation cycle (M_pre = 28.44, M_post = 18.56; p = 0.001, d = 0.80, 95% CI (0.36, 1.25)), with stable scores across all domains over one year. Improvements were most notable in memory, speech, and mood. Conclusions: TPS appears to be a generally safe and feasible add-on treatment for AD, although careful patient selection and monitoring are advised. While a considerable number of participants were lost to follow-up for various reasons, adverse events and lack of treatment effect were unlikely primary causes. A multifocal stimulation approach (F-TOP2) is proposed to enhance effects across more cognitive domains. Full article

High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of ovarian cancer, accounting for approximately 70% of cases. This study investigates genetic mutations and their associations with overall survival (OS), complete cytoreduction (R0), and platinum response in patients undergoing either primary debulking surgery followed by adjuvant chemotherapy (PDS) or neoadjuvant chemotherapy followed by interval debulking surgery (NACT). Genetic analysis was performed on 43 primary HGSOC tumor samples using targeted massive parallel sequencing via next-generation sequencing (NGS). Clinical and molecular data were evaluated collectively and through subgroup comparisons between PDS and NACT cohorts. All analyzed samples harbored genetic alterations. Univariate survival analysis revealed that the total number of mutations (p = 0.0035), as well as mutations in HRAS (p = 0.044), FLT3 (p = 0.023), TP53 (p = 0.03), and ERBB4 (p = 0.007), were significantly associated with poorer OS. Multivariate Cox regression integrating clinical and molecular data confirmed that ERBB4 mutations are independently associated with adverse outcomes. These findings reveal a distinctive mutational landscape between the PDS and NACT groups and suggest that ERBB4 alterations may define a particularly aggressive tumor phenotype. This study contributes to a deeper understanding of HGSOC biology and may support the development of novel therapeutic targets and personalized treatment strategies in the context of precision oncology. Full article

High demand for sustainable solutions in the construction industry determines the significant relevance of developing new eco-friendly composites with a reduced carbon impact on the environment. The main aim of this study is to investigate the possibility and efficiency of using technical sulfur (TS) as a modifying additive for geopolymer composites and to select the optimal content of polypropylene fiber (PF). To assess the potential of TS, experimental samples of geopolymer solutions based on metakaolin and fly ash were prepared. The TS content varied from 0% to 9% by weight of binder in 3% increments. In the first stage, the density, compressive and flexural strength, capillary water absorption and microstructure of hardened geopolymer composites were tested. The TS additive in an amount of 3% was the most effective and provided an increase in compressive strength by 12.6%, flexural strength by 12.8% and a decrease in capillary water absorption by 18.2%. At the second stage, the optimal PF content was selected, which was 0.75%. The maximum increases in strength properties were recorded for the composition with 3% TS and 0.75% PF: 8% for compression and 32.6% for bending. Capillary water absorption decreased by 12.9%. The geopolymer composition developed in this work, modified with TP and PF, has sufficient mechanical and physical properties and can be considered for further study in order to determine its competitiveness with cement composites in real construction practice. Full article

The main soil type in the Sanjiang Plain of Northeast China, dryland albic soil is of great significance for studying nutrient distribution characteristics. This study focuses on 852 Farm in the typical dryland albic soil area of the Sanjiang Plain, using a combination of paired t-test, geostatistics, correlation analysis, and principal component analysis to systematically reveal the spatial differentiation of soil nutrients in the black soil layer and white clay layer of dryland albic soil, and to clarify the impact mechanism of plow layer nutrient characteristics on crop productivity. The results show that the nutrient content order in both the black and white clay layers is consistent: total potassium (TK) > organic matter (OM) > total nitrogen (TN) > total phosphorus (TP) > alkali-hydrolyzable nitrogen (HN) > available potassium (AK) > available phosphorus (AP). Both layers exhibit a spatial pattern of overall consistency and local differentiation, with spatial heterogeneity dominated by altitude gradients—nutrient content increases with decreasing altitude. Significant differences exist in nutrient content and distribution between the black and white clay layers, with the comprehensive fertility of the black layer being significantly higher than that of the white clay layer, particularly for TN, TP, TK, HN, and OM contents (effect size > 8). NDVI during the full maize growth period is significantly positively correlated with TP, TN, AK, AP, and HN, and the NDVI dynamics (first increasing. then decreasing) closely align with the peak periods of available nitrogen/phosphorus and crop growth cycles, indicating a strong coupling relationship between vegetation biomass accumulation and nutrient availability. These findings provide important references for guiding rational fertilization, agricultural production layout, and ecological environmental protection, contributing to the sustainable utilization of dryland albic soil resources and sustainable agricultural development. Full article

Objectives: To investigate the efficacy and underlying mechanisms of IBCar’s biological activity in breast cancer models, both in cell culture and in mice, and to compare its effects on cancer versus normal cells. Methods: The cytotoxicity of IBCar was evaluated using the MTS assay to assess metabolic activity and the clonogenic assay to determine reproductive integrity. The impact of IBCar on microtubule integrity, mitochondrial function, and multiple signaling pathways was analyzed using Western blotting, microarray analysis, and live cell imaging. The therapeutic effectiveness of orally administered IBCar was assessed in a transgenic mouse model of Luminal B breast cancer and in mice implanted with subcutaneous triple-negative breast cancer xenografts. Results: IBCar demonstrated potent cytotoxicity across a diverse panel of breast cancer cell lines, including those with mutant or wild-type TP53, and cell lines with short and long doubling times. Comparative analysis revealed distinct responses between normal and cancer cells, including differences in IBCar’s effects on the mitochondrial membrane potential, endoplasmic reticulum stress and activation of cell death pathways. In breast cancer cells, IBCar was cytotoxic at nanomolar concentrations, caused irreversible microtubule depolymerization leading to sustained mitochondrial dysfunction, endoplasmic reticulum stress, and induced apoptosis. In normal cells, protective mechanisms included reversible microtubule depolymerization and activation of pro-survival signaling via the caspase-8 and riptosome pathways. The therapeutic potential of IBCar was confirmed in mouse models of Luminal B and triple negative BC, where it exhibited strong antitumor activity without detectable toxicity. Conclusions: These findings collectively support IBCar as a promising, effective, and safe therapeutic candidate for breast cancer treatment. Full article

Background/Objectives: The 2019 WHO classification redefined high-grade gastrointestinal neuroendocrine neoplasms (GI NENs), encompassing not only poorly differentiated neuroendocrine carcinomas (NECs), but also well-differentiated grade 3 neuroendocrine tumors (NETs G3). Since both subtypes share a Ki-67 index > 20%, distinguishing them based solely on morphology is challenging. Prior studies have shown TP53 alterations in NECs but not in NETs. This study aimed to evaluate clinico-morphological parameters and the immunohistochemical (IHC) expression of p53 in high-grade GI NENs to identify relevant correlations. Methods: Tumors were stratified by Ki-67 index into two groups: >20–50% and >50%. p53 IHC expression was assessed as “wild-type” (1–20% positive tumor cells) or “non-wild-type” (absence or >20% positivity). Correlations were analyzed between Ki-67, p53 status, and various pathological features. Results: Significant correlations were found between the Ki-67 index and maximum tumor size, pT stage, lymphovascular invasion, perineural infiltration, and diagnostic classification. Similarly, p53 immunohistochemical status was significantly associated with lymphovascular invasion, lymph node metastasis, and tumor classification (NET G3 versus NEC, including NEC components of MiNENs). Conclusions: The findings support the value of Ki-67 and p53 as complementary biomarkers in the pathological evaluation of high-grade GI NENs. Their significant associations with key morphological parameters support their utility in differentiating NETs G3 from NECs, particularly in cases showing overlapping histological features. The immunohistochemical profile of p53 may serve as a useful diagnostic adjunct in routine practice. Full article

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article

Many hospitals still lack digital traceability in hygiene and cleaning management, leading to operational inefficiencies and inconsistent quality control. This study aims to establish cleaning and hygiene processes in healthcare services that are planned in accordance with standards, as well as to enhance the traceability and sustainability of these processes through digitalization. This study proposes a Hyperledger Fabric-based blockchain architecture to establish a reliable and transparent quality assurance system in process management. The proposed Quality Assurance Model utilizes digital technologies and IoT-based RFID devices to ensure the transparent and reliable monitoring of cleaning processes. Operational data related to cleaning processes are automatically recorded and secured using a decentralized blockchain infrastructure. The permissioned nature of Hyperledger Fabric provides a more secure solution compared to traditional data management systems in the healthcare sector while preserving data privacy. Additionally, the execute–order–validate mechanism supports effective data sharing among stakeholders, and consensus algorithms along with chaincode rules enhance the reliability of processes. A working prototype was implemented and validated using Hyperledger Caliper under resource-constrained cloud environments, confirming the system’s feasibility through over 100 TPS throughput and zero transaction failures. Through the proposed system, cleaning/hygiene processes in patient rooms are conducted securely, contributing to the improvement of quality standards in healthcare services. Full article

This study was developed to identify the optimal (most cost-effective) strategies to reduce sediment and phosphorus loadings in the Upper Soldier Creek, Kansas, USA, watershed using the Watershed Management Optimization Support Tool (WMOST) suite of programs. Under average precipitation, loading targets for upland total phosphorus (TP) could be met with use of grassed swales for treating urban area runoff and of contouring for agricultural runoff. For a wet year, the same target could be met, but with use of a sand filter with underdrain for the urban runoff. Both annual and daily TP loading targets from Total Maximum Daily Loads (TMDLs) were exceeded in simulations of best management practice (BMP) solutions for 14 alternative future climate scenarios. We expanded the set of BMPs to include stream bank stabilization (physical plus riparian restoration) and two-stage channel designs, but upland loading targets could not be met for either TP or total suspended solids (TSS) under any precipitation conditions. An optimization scenario that simulated the routing of flows in excess of those treated by the upland BMPs to an off-channel treatment wetland allowed TMDLs to be met for an average precipitation year. WMOST can optimize cost-effectiveness of BMPs across multiple scales and climate scenarios. Full article

Dual-active bridge (DAB) converters have emerged as a preferred topology in electric vehicle charging and energy storage applications, owing to their structurally symmetric configuration and intrinsic galvanic isolation capabilities. However, conventional triple-phase shift (TPS) control strategies face significant challenges in maintaining high efficiency across ultra-wide output voltage and load ranges. To exploit the inherent structural symmetry of the DAB topology, a symmetric optimization strategy based on triple-phase shift (SOS-TPS) is proposed. The method specifically targets the forward buck operating mode, where an optimization framework is established to minimize the root mean square (RMS) current of the inductor, thereby addressing both switching and conduction losses. The formulation explicitly incorporates zero-voltage switching (ZVS) constraints and operating mode conditions. By employing the Karush–Kuhn–Tucker (KKT) conditions in conjunction with the Lagrange multiplier method (LMM), the refined control trajectories corresponding to various power levels are analytically derived, enabling efficient modulation across the entire operating range. In the medium-power region, full-switch ZVS is inherently satisfied. In the low-power operation, full-switch ZVS is achieved by introducing a modulation factor λ, and a selection principle for λ is established. For high-power operation, the strategy transitions to a conventional single-phase shift (SPS) modulation. Furthermore, by exploiting the inherent symmetry of the DAB topology, the proposed method reveals the symmetric property of modulation control. The modulation strategy for the forward boost mode can be efficiently derived through a duty cycle and voltage gain mapping, eliminating the need for re-derivation. To validate the effectiveness of the proposed SOS-TPS strategy, a 2.3 kW experimental prototype was developed. The measured results demonstrate that the method ensures ZVS for all switches under the full load range, supports ultra-wide voltage conversion capability, substantially suppresses RMS current, and achieves a maximum efficiency of 97.3%. Full article

Breast-conserving surgery followed by external beam Radiotherapy (RT) is a standard approach for early-stage Breast Cancer (BC). This retrospective study aims to determine the risk of RT-induced lung cancer for both standard and hypofractionated treatments. Fifty-eight Sicilian women treated at Humanitas Istituto Clinico Catanese (Misterbianco, Italy) between 2015 and 2021 with standard fractionated 3D-CRT (50 Gy in 2 Gy/fraction) were included. All treatment plans were designed using a hypofractionated schedule (42.56 Gy in 2.66 Gy/fraction). An Eclipse™ plug-in script was developed using the Eclipse Scripting Application Programming Interface (ESAPI) to extract patient and treatment data from the Treatment Planning System and compute Organ At Risk (OAR) volume, Organ Equivalent Dose (OED), Excess Absolute Risk (EAR), and Lifetime Attributable Risk (LAR) using the Schneider Mechanistic Model and reference data from regional populations, A-bomb survivors, and patients with Hodgkin’s Disease (HD). The OED distributions exhibited a statistically significant shift toward higher values in standard fractionated plans (p < 0.01, one-tailed paired Student’s t-test), leading to increased EAR and LAR. These results indicate that hypofractionated treatment may lower the risk of radiation-induced lung cancer. The feasibility of a priori risk estimation was evaluated by integrating the script into the TPS, allowing rapid comparison of SF and HF plans during planning. Full article

The electrooxidation (EO) of three important environmental contaminants, anticorrosive 1H-benzotriazole (BTA), plasticizer dibutyl phthalate (DBP), and non-ionic surfactant Triton X-100 (tert-octylphenoxy[poly(ethoxy)] ethanol, t-OPPE), was studied as a possible means to improve their elimination from wastewaters, which are an important emission source. EO was performed in a batch reactor with a boron-doped diamond (BDD) anode and a stainless steel cathode. Different supporting electrolytes were tested: NaCl, H₂SO₄, and Na₂SO₄. Results were analysed from the point of their efficacy in terms of degradation rate, kinetics, energy consumption, and transformation products. The highest degradation rate, shortest half-life, and lowest energy consumption was observed in the electrolyte H₂SO₄, followed by Na₂SO₄ with only slightly less favourable characteristics. In both cases, degradation was probably due to the formation of persulphate or sulphate radicals. Transformation products (TPs) were studied mainly in the sulphate media and several oxidation products were identified with all three contaminants, while some evidence of progressive degradation, e.g., ring-opening products, was observed only with t-OPPE. The possible reasons for the lack of further degradation in BTA and DBP are too short of an EO treatment time and perhaps a lack of detection due to unsuitable analytical methods for more polar TPs. Results demonstrate that BDD-based EO is a robust method for the efficient removal of structurally diverse organic contaminants, making it a promising candidate for advanced water treatment technologies. Full article

Fibrate pharmaceuticals (fibrates), as a widespread class of emerging contaminants, pose potential risks to both ecological systems and human health. The photocatalytic system based on nitrogen (N) and fluorine (F) co-doped TiO₂ nanotube arrays (NF-TNAs) provides a renewable solution for fibrate pharmaceutical removal from water, powered by inexhaustible sunlight. In this study, the degradation of two typical fibrates, i.e., bezafibrate (BZF) and ciprofibrate (CPF), under simulated sunlight irradiation through NF-TNAs were investigated. The photocatalytic degradation of BZF/CPF was achieved through combined radical and non-radical oxidation processes, while the generation and reaction mechanisms of associated reactive oxygen species (ROS) were examined. Electron paramagnetic resonance detection and quenching tests confirmed the existence of h⁺, •OH, O₂^•−, and ¹O₂, with O₂^•− playing the predominant role. The transformation products (TPs) of BZF/CPF were identified through high-resolution mass spectrometry analysis combined with quantum chemical calculations to elucidate the degradation pathways. The influence of co-existing ions and typical natural organic matters (NOM) on BZF/CPF degradation were also tested. Eventually, the ecological risk of BZF/CPF transformation products was assessed through quantitative structure–activity relationship (QSAR) modeling, and the results showed that the proposed photocatalytic system can largely alleviate fibrate toxicity. Full article

Background/Objectives: Autism spectrum disorders (ASDs) are neurodevelopmental conditions with early onset of clinical manifestations. ASD etiology is highly heterogeneous, with genetic factors being strong determinants of the behavioral problems and neurodevelopmental deficits. Fragile X syndrome (FXS) (OMIM #300624), caused by the transcriptional silencing of the FMR1 gene, represents the most common monogenic cause of autism. Our study included 226 boys with a diagnosis of ASD, for a systematic screening of genetic and epigenetic defects in the FMR1 gene promoter in a Romanian pediatric cohort. Methods: The methods, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and triplet-primed PCR (TP-PCR)/melt curve analysis (MCA), were chosen for their ability to detect the methylation anomalies (the former) as well as repeat expansions in the FMR1 promoter (the latter). Results: Both methods used in our screening generated concordant results, detecting FMR1 full mutation in 4 out of 226 patients (~1.8%). This yield is similar to data obtained in larger studies. Three out of four boys presented the typical clinical features, in correlation with genetic findings. Conclusions: The combined use of MS-MLPA and TP-PCR/MCA-based assay was, in our experience, useful to fully describe the genetic defects responsible for FXS. A significant variability of clinical presentations was observed in our small group of children with FXS, from mild to severe intellectual disability and from atypical to characteristic dysmorphic features, as well as various behavioral problems. Full article