Search Results (879)

Background/Objectives: Targeting ABL tyrosine kinase (TK) remains a cornerstone of chronic myeloid leukemia (CML) therapy. Methods: In this study, a series of novel 4-((2-(4-(aryl)thiazol-2-yl)hydrazineylidene)methyl)-N,N-diphenylaniline derivatives (1–12) were synthesized through the reaction of 2-(4-(diphenylamino)benzylidene)hydrazine-1-carbothioamide (intermediate A) with substituted 2-bromo-1-arylethanones. Cytotoxic activity was evaluated in K562 CML cells using the MTT assay. The most active compound was further assessed in HL-60 acute myeloid leukemia (AML) cells and healthy peripheral blood mononuclear cells (PBMCs). Apoptosis induction was analyzed by Annexin V/ethidium homodimer staining, while ABL TK inhibition was determined using the ADP-Glo kinase assay. Molecular docking studies were performed to investigate binding interactions within the ATP-binding site of ABL TK, and pharmacokinetic properties were also predicted. Results: Intermediate A demonstrated superior antiproliferative activity compared to derivatives 1–12 and exhibited cytotoxicity comparable to imatinib in K562 cells (IC₅₀ = 6.15 ± 1.26 µM vs. 5.14 ± 1.44 µM, respectively). In HL-60 cells, intermediate A showed an IC₅₀ of 12.04 ± 1.70 µM, similar to imatinib. Notably, intermediate A displayed enhanced selectivity toward K562 cells over PBMCs (SI = 12.9) relative to imatinib (SI = 6.2). The compound significantly induced apoptosis in K562 cells and inhibited ABL TK activity. Docking studies revealed a distinct binding orientation within the ATP-binding pocket of ABL TK. The compound showed acceptable predicted physicochemical and ADME characteristics based on in silico analysis. Conclusions: Intermediate A emerges as a significant anti-CML candidate exhibiting potent cytotoxic, apoptotic, and moderate ABL TK inhibitory activity, together with a favorable selectivity profile. Full article

Background/Objectives: Advanced glycation end products (AGEs) and oxidative stress increase with aging and are implicated in Alzheimer’s disease (AD). We developed an anti-glycation blend using LC-MS-based screening and assessed its effects on oxidative and glycation-related biomarkers in humans. Methods: Twelve candidate compounds were screened in a BSA–glucose model using LC-MS peptide mapping to quantify lysine glycation and rank inhibitory activity. The top candidates were combined into a three-compound blend (quercetin, rutin, genistein). In a randomized, double-blind, placebo-controlled 3-month trial, older healthy adults (n = 30) and individuals with AD (n = 30) received anti-AGE blend (n = 15 in older group and n = 15 in AD group) or placebo (n = 15 in older group and n = 15 in AD group). Serum malondialdehyde and urinary Nε-(carboxymethyl)lysine were measured pre–post intervention. Pre/post and between-arm comparisons within each population were performed using REML ANOVA with Tukey post hoc tests. Serum MDA (malondialdehyde) and urinary CML (Nε-(carboxymethyl)lysine) were prespecified biomarker outcomes and are reported here as co-primary biomarker endpoints. No formal a priori sample size calculation was performed; the study size was feasibility-based. Results: LC-MS screening identified genistein, quercetin, and rutin as the most consistent inhibitors of glucose-driven BSA glycation. In older healthy adults, serum MDA decreased after anti-AGE supplementation (p < 0.001) and differed from the placebo (p < 0.01), while no change was observed within the placebo group (ns). In the AD cohort, MDA did not change significantly from baseline within either arm (ns), but post-intervention MDA was lower in anti-AGE than in the placebo (p < 0.05). Urinary CML was unchanged in older healthy adults (ns in both arms), whereas in AD, it decreased after anti-AGE supplementation (p < 0.01) and differed from the placebo (p < 0.05). Conclusions: A screening-guided anti-glycation blend supplementation was associated with changes in selected biomarkers in humans: MDA decreased across cohorts, while CML decreased selectively in AD. Larger trials with extended biomarker panels and LC–MS/MS confirmation are warranted. Full article

Background: Myeloid sarcoma (MS) is a malignant extramedullary tumor that occurs in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML). The standard first-line treatment for MS is intensive chemotherapy according to the AML protocol, regardless of bone marrow involvement. The role of allogeneic hematopoietic stem cell transplantation (alloHSCT) in the treatment of pediatric patients with MS requires further investigation. The aim of the study was to evaluate treatment outcomes for MS in pediatric patients with a focus on assessing the impact of allogeneic hematopoietic stem cell transplantation (alloHSCT) on treatment efficacy. Material and Methods: The study included 64 patients aged 0 to 19 years from 15 pediatric oncology centers in Poland who were diagnosed with MS between 1998 and 2024. An Excel database was created to collect data on clinical features and treatment methods and outcomes. Results: The probability of 5-year overall survival (pOS) for the entire cohort was 0.63 ± 0.07, while the 5-year event-free survival (pEFS) and 5-year relapse-free survival (pRFS) were 0.62 ± 0.07 and 0.72 ± 0.07, respectively. Treatment outcomes were compared between patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (ICR) (n1 = 17/64; 27%) and those who did not receive alloHSCT (n2 = 47/64; 73%). In the alloHSCT group (n1), the estimated survival probabilities were pOS = 0.49 ± 0.13, pEFS = 0.44 ± 0.14, and pRFS = 0.40 ± 0.14. In the non-alloHSCT group (n2), these values were pOS = 0.68 ± 0.08, pEFS = 0.68 ± 0.08, and pRFS = 0.84 ± 0.06. The difference in pRFS between groups n1 and n2 was statistically significant (p = 0.0049). Extramedullary relapses were more frequently observed in patients who had undergone allogeneic hematopoietic stem cell transplantation (alloHSCT) (p = 0.0001). Conclusions: Allogeneic hematopoietic stem cell transplantation (alloHSCT) does not improve the outcome of patients with MS. Further research is needed to identify effective strategies for sustaining remission in patients with MS after alloHSCT. Full article

Objective: This study aimed to investigate erythrocyte morphological alterations in hematological malignancies, with particular emphasis on structural differences among leukemia subtypes and anemia. Materials and Methods: Peripheral blood samples were obtained from 60 patients, including individuals with anemia (n = 10), acute lymphoblastic leukemia (ALL, n = 15), acute myeloid leukemia (AML, n = 15), chronic lymphocytic leukemia (CLL, n = 15), and chronic myeloid leukemia (CML, n = 5), as well as 10 healthy controls. Erythrocyte morphology was evaluated using light microscopy and scanning electron microscopy. Morphological abnormalities, including loss of biconcavity, poikilocytosis, echinocyte transformation, burr cells, and stomatocytes, were assessed in accordance with International Council for Standardization in Haematology (ICSH)-based morphological definitions. Results: Distinct erythrocyte morphological alterations were observed across disease groups. AML cases demonstrated pronounced central depression-like or perforation-like structures and hypochromasia. Lymphoid malignancies, particularly ALL and CLL, exhibited increased echinocyte formation, whereas chronic leukemias showed a higher prevalence of stomatocytes and cup-shaped cells. Quantitative scoring indicated that loss of biconcavity was most prominent in anemia, followed by AML, CML, ALL, and CLL. Poikilocytosis was most frequent in anemia, followed by ALL, CLL, AML, and CML. Conclusions: The findings indicate that erythrocyte shape alterations are more heterogeneous and prominent in lymphoid leukemias, whereas myeloid leukemias exhibit distinct ultrastructural membrane abnormalities. Although studies focusing on erythrocyte morphology in leukemia remain limited, the present results provide a foundational morphological reference dataset that may support the development and validation of artificial intelligence-based diagnostic approaches. Further studies involving larger cohorts and expanded imaging analyses are warranted to improve diagnostic accuracy and translational applicability. Full article

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has been added to the World Health Organization’s list as a high-priority pathogen for which new antibiotics are urgently needed. Herein, we investigated the association between resistance/virulence genes and high-risk CRPA clinical isolates by whole genome sequencing (WGS). Methods: Between 2019 and 2025, twenty-six CRPA strains from patients hospitalized in the “Renato Dulbecco” University Hospital were characterized. WGS analysis was performed using the next generation sequencing (NGS) technique. Multi-locus sequence typing (MLST) prediction was performed. Antibiotic resistance genes were detected using Antibiotic Resistance Gene-ANNOTation, Comprehensive Antibiotic Resistance Database, and ResFinder. Virulence genes were identified by the Virulence Factor Database. Results: The MLST analysis detected 14 different sequence types (ST). The 26 strains exhibited the same resistome profile: aac(3)-Ic, aphA15, catB7, catB10, cmlA, blaCARB, blaVIM-1, and tetG genes. The genes encoding enzymes involved in resistance to chloramphenicol and beta-lactams were found in all isolates using the three databases. Biofilm formation genes, metalloproteinase, chemotaxis, fimbriae, and pyoverdine were identified in all strains. Genes of the type III secretion system exoS, exoT, exoU, and exoY were found in 46.15%, 84.61%, 53.84%, and 84.61% of the strains, respectively. Conclusions: The analysis of the 26 clinical isolates showed high clonal heterogeneity, with a predominance of ST235, a high-risk clone associated with multiple resistances. Interestingly, cefiderocol resistance was carried by 4/8 isolates belonging to the ST235 strain. The surveillance based on resistome and virulome analysis could monitor the dynamic evolution of high priorityhigh-priority pathogens to guide clinical treatment and to adapt healthcare control measures, limiting their spread in the near future. Full article

Polymer-based insulation materials are widely used to enhance the energy efficiency of buildings; however, their growing application raises concerns related to resource use and end-of-life management. Rigid polyurethane (PUR) foams are key core materials in structural insulated panels due to their favorable thermal and mechanical performance, yet their life cycle environmental impacts—particularly at end-of-life—remain insufficiently quantified. In this study, a cradle-to-grave life cycle assessment (LCA) of PUR-based insulation used in structural insulated panel systems is conducted in accordance with ISO 14040/44 and EN 15804 standards. The assessment is performed using Sphera LCA software (version: GaBi 10.5) and the CML 2016 impact assessment method. Formulation-level variations in rigid PUR foams, including changes in methylene diphenyl diisocyanate content and pentane blowing agent ratio, are explicitly incorporated to evaluate their influence on key environmental impact categories. The results indicate that increasing pentane content leads to higher global warming potential, while this effect may be mitigated or intensified by concurrent changes in diisocyanate content and foam density in fully formulated systems. Three end-of-life scenarios—landfilling, incineration with energy recovery, and mechanical recycling—are analyzed. The findings provide material-level, decision-relevant insights that support environmentally informed formulation strategies and contribute to the development of more circular polymer-based insulation solutions for the built environment. Full article

Chronic myeloid leukemia (CML) has undergone a significant shift over the past two decades, transitioning from a fatal malignancy to a chronic, highly manageable disease with near-normal life expectancy for most patients. This transformation has been driven by the development of BCR-ABL1-targeted tyrosine kinase inhibitors (TKIs), which have enabled durable disease control and deep molecular responses (DMRs) in the majority of patients with chronic-phase CML. As long-term survival outcomes have plateaued across available agents, contemporary management has shifted beyond disease suppression toward optimizing long-term safety, quality of life, and the achievement of treatment-free remission (TFR). This review summarizes current evidence on molecular monitoring strategies, the comparative efficacy and toxicity profiles of first-, second-, and third-generation TKIs, and emerging advances in response assessment. Patient-centered TKI selection is discussed in the context of cardiovascular risk, comorbidities, treatment tolerability, and survivorship goals, reflecting the growing emphasis on individualized therapy in chronic-phase CML. Molecular monitoring strategies are examined in parallel, highlighting the clinical importance of early and sustained DMRs in guiding therapeutic decisions and TFR eligibility. Although RT-qPCR remains the standard for molecular monitoring, emerging high-sensitivity techniques such as digital droplet PCR and next-generation sequencing provide complementary value by improving the detection of low-level residual disease, refining risk stratification, and enabling earlier identification of resistance. Emerging therapeutic strategies and advances in response assessment further highlight ongoing efforts to enhance the depth and durability of remission while minimizing long-term toxicity. These developments support a more precise, individualized, and outcome-driven approach to modern CML management. Full article

In this paper we present a low-noise, high-frame-rate global shutter CMOS image sensor with UHD resolution (3840 × 2160), targeting high-speed machine vision applications. The sensor (ForzaFAST581) supports video capture at up to 1141 FPS at 12 bits and 1694 FPS at 8 bits at full resolution, consuming a total power of 5.5 W. Fabricated in a 65 nm, four-metal BSI process, the imager features a 5 µm voltage-domain global shutter pixel with dual-gain capability for improved dynamic range and a read noise of 3.04 e⁻ in global shutter and 2.15 e⁻ in rolling shutter mode for high-gain at maximum frame rate operation. For compact camera integration and low power consumption, the sensor is designed to stream video through 16 CML data ports, each operating at 7.44 Gbps, achieving a total aggregate throughput of 119 Gbps. Additionally, the sensor supports selectable output bit depths—8-bit, 10-bit, and 12-bit—allowing frame rate optimization based on application-specific requirements. Full article

With the intensification of global climate change, environmental issues such as soil salinization and drought have exerted an increasingly prominent impact on plants. Tibetan peach (Amygdalus mira), a rare native tree species of the genus Amygdalus in the Rosaceae family, possesses extremely strong tolerance to cold, drought, and disease stress. In the previous study, we found that the protein abundance of a calcium-binding protein, AmCML24, was significantly upregulated in Tibetan peach under drought stress, leading us to hypothesize that it plays an important role in the molecular mechanisms underlying plant responses to abiotic stresses. Therefore, this study focuses on AmCML24, aiming to preliminarily characterize the stress-tolerant function of AmCML24 and explore its biological role in plant tolerance to saline–alkali and drought stresses. Results demonstrated that AmCML24 responds to multiple abiotic stresses. Yeast and Arabidopsis thaliana lines overexpressing AmCML24 exhibited enhanced tolerance to NaCl, NaHCO₃, and mannitol stresses, with a significant upregulation in the expression of stress-responsive genes. This study lays a solid foundation for deciphering the stress regulatory network of Tibetan peach and elucidating the biological function of AmCML24, while also providing a scientific basis for the genetic improvement, exploitation, and utilization of Tibetan peach germplasm resources. Full article

Calmodulin-like proteins (CMLs) are key mediators of plant calcium signaling and participate in abiotic stress responses, but their functions in potato remain poorly understood. Here, we systematically identified 62 StCML genes in potato via genome-wide analysis, which were phylogenetically clustered into seven clades and unevenly distributed across 12 chromosomes. Synteny analysis indicated that tandem and segmental duplications drove StCML family expansion, while promoter cis-element analysis suggested their involvement in phytohormone signaling and stress responses. Transcriptomic data showed StCMLs exhibited tissue-specific expression (high in roots, flowers, stamens) and were transcriptionally induced by drought, salt, and abscisic acid (ABA). Heterologous overexpression of StCML50 in Arabidopsis enhanced drought tolerance, as evidenced by improved germination, root elongation, and survival compared to wild-type. Physiologically, StCML50 overexpression increased proline accumulation, boosted antioxidant enzyme (SOD, CAT, POD) activities, and reduced malondialdehyde (MDA) levels under drought. Additionally, transgenic lines showed increased ABA sensitivity. This study provides insights into the potato CML gene family’s evolution and regulatory mechanisms, offering a valuable genetic resource for potato stress tolerance improvement. Full article

Estimating how crop yield responds to site-specific nitrogen (N) fertilization is essential for maximizing yield potential under variable field conditions. However, classical Machine Learning (ML) approaches applied to observational farm data primarily focus on yield prediction and often fail to recover causal N response due to confounding arising from non-random fertilizer application. In this study, we develop and evaluate a Causal Machine Learning (CML) framework to estimate heterogeneous N treatment effects under real commercial rice-farming conditions in the Axios River Plain, Greece. The proposed approach combines Double Machine Learning (DML) with remote sensing, soil, climatic, and management data to adjust for confounding and identify causal relationships between N inputs, Leaf Nitrogen Concentration (LNC), and yield. A doubly robust (DR) learner is used to estimate yield sensitivity to N at key agronomic thresholds, while a Causal Forest model leverages LNC to assess crop physiological N status. Results demonstrate that the CML-based framework outperforms conventional XGBoost predictive models in identifying field plots that are responsive to additional N. By integrating causal effect estimation with plant-status information, the proposed decision support system identifies zones where yield gains can be achieved through targeted N increases while avoiding overfertilization in non-responsive areas. Full article

With the increasing frequency extreme weather events associated with climate change, real-time monitoring of rainfall intensity is critical for water resource management, disaster warning, and other applications. Traditional methods, such as ground-based rain gauges, radar, and satellites, face challenges like high costs, low resolution, and monitoring gaps. This study proposes a novel real-time rainfall intensity monitoring method based on deep learning and audio signal processing, using acoustic features from rainfall to predict intensity. Conducted in the semi-arid region of Northwest China, the study employed a custom-designed sound collection device to capture acoustic signals from raindrop-surface interactions. The method, combining multi-feature extraction and regression modeling, accurately predicted rainfall intensity. Experimental results revealed a strong linear relationship between sound pressure and rainfall intensity (r = 0.916, R² = 0.838), with clear nonlinear enhancement of acoustic energy during heavy rainfall. Compared to traditional methods like CML and radio link techniques, the acoustic approach offers advantages in cost, high-density deployment, and adaptability to complex terrain. Despite some limitations, including regional and seasonal biases, the study lays the foundation for future improvements, such as expanding sample coverage, optimizing sensor design, and incorporating multi-source data. This method holds significant potential for applications in urban drainage, agricultural irrigation, and disaster early warning. Full article

Endophytic fungi enhance plant growth and stress resilience, yet their molecular roles in the roots of the endangered tree Phoebe bournei remain unclear. A comparative RNA-seq analysis was performed on root transcriptomes from wild, endophyte-colonized adult trees (OT) and axenically grown seedlings (ST). Unmapped reads were analyzed against the NCBI nucleotide (NT) database using BLASTN (v2.17.0), revealing Rhizophagus irregularis as the predominant endophytic fungus. Differential expression analysis identified 5891 DEGs, which were significantly enriched in pathways related to plant–pathogen interactions, phenylpropanoid biosynthesis, plant hormone signal transduction, and MAPK signaling. Key upregulated genes included PbMPK3, PbCML42, PbCML41.2, and PbGSTU28, suggesting enhanced ROS scavenging, calcium signaling, and defense activation. RT-qPCR validation confirmed the transcriptomic trends for selected genes. Our findings reveal that root endophytic fungi modulate a coordinated network involving immune priming, phytohormone regulation, and redox homeostasis, thereby supporting root development and enhancing resistance to biotic and abiotic stresses in P. bournei. This study provides foundational molecular insights into beneficial plant–endophyte interactions and identifies candidate genes that are valuable for the conservation and breeding of this threatened species. Full article

Background: Macrocytosis commonly develops during imatinib therapy, but its relationship with cytogenetic and molecular outcomes in chronic myeloid leukemia (CML) remains unclear. We investigated whether increases in mean corpuscular volume (MCV) during imatinib treatment are associated with response depth and treatment persistence. Methods: In this retrospective study, we analyzed 101 adults with chronic-phase CML treated with a stable imatinib dose of 400 mg/day for at least 12 months. Patients with conditions that could confound MCV (hydroxyurea exposure, megaloblastic anemia, hypothyroidism, chronic liver disease, alcoholism) were excluded. Complete cytogenetic response (CCyR) and major molecular response (MMR) were assessed by conventional karyotyping and the BCR-ABL1 International Scale, respectively. Increased MCV was defined as MCV > 100 fL after six months of therapy, persisting thereafter. Associations between MCV dynamics, response, and switching to second-generation tyrosine kinase inhibitors were evaluated. Results: Twenty patients (20%) developed increased MCV. Overall, 86 patients (85%) achieved CCyR and 70 (69%) achieved MMR. All patients with increased MCV attained CCyR, compared with 66 of 81 (81%) without MCV elevation (p = 0.037), while MMR rates were 90% versus 64% (p = 0.030). During a median follow-up of 69 months, treatment modification was required in 1 of 20 (5%) patients with increased MCV versus 25 of 81 (31%) in the non-increased group (p = 0.018). Conclusions: MCV elevation during imatinib therapy is associated with deeper molecular response and reduced need for treatment modification. MCV dynamics may serve as an inexpensive pharmacodynamic marker to support risk assessment and guide monitoring in chronic-phase CML. Full article

Background: Honeybees sustain vital ecological roles through foraging behavior, which provides pollination services and is likely regulated by dopamine signaling coupled to brain energy metabolism. However, the genetic and metabolic mechanisms underlying this regulation remain unclear. Methods: We treated honeybee workers with the dopamine receptor agonist bromocriptine and employed an integrative approach, combining liquid chromatography–mass spectrometry (LC–MS) metabolomics with single-nucleus RNA sequencing (snRNA-seq). Results: Metabolomics revealed increased levels of N6-carboxymethyllysine (CML) and a coordinated shift in central carbon metabolites, including higher glucose, pyruvate, and lactate within glycolysis, and ribose-5-phosphate in the pentose phosphate pathway (PPP). Integration with transcriptomics showed heterogeneous responses: glial cells exhibited higher glycolysis pathway scores and upregulated hexokinase expression compared to neurons, whereas major PPP enzymes were upregulated in both glial and neuronal subsets. Conclusions: These findings suggest that dopamine receptor activation is associated with altered whole-brain metabolic profiles and concurrent, cell-type-specific upregulation of glycolytic and PPP enzyme genes, particularly in glia. This study characterizes these neuro-metabolic associations, offering insights into the cellular and metabolic basis of foraging behavior in worker bees. Full article