Search Results (806)

Ferrocene (Fc), a redox-active organometallic scaffold, has attracted significant attention in medicinal chemistry due to its favorable physicochemical and pharmacological properties. The present study explores the therapeutic potential of novel Fc-functionalized analogues of imatinib and nilotinib, aimed at targeting BCR-ABL1+ chronic myeloid leukemia (CML) cells. A series of Fc-based derivatives (compounds 6, 9, 14, and 18) were synthesized by systematically substituting key pharmacophoric regions of the parent tyrosine kinase inhibitors with Fc units. The antiproliferative activity of these compounds was evaluated against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, and LAMA-84), with imatinib serving as a reference drug. Biological assays revealed distinct structure–activity relationships. Compounds 6 and 9 demonstrated superior activity against the K-562 cell line, while compounds 14 and 18 exhibited enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib. Selectivity assays further indicated favorable toxicity profiles of compounds 9 and 14 toward malignant versus non-malignant cells. Molecular docking studies supported these findings, showing that Fc substitution alters binding interactions within the c-Abl kinase ATP-binding site while retaining key stabilizing contacts. Computationally predicted LEs showed strong correlation with experimental data, especially for K-562 and LAMA-84 cells, confirming the kinase as a relevant target. Full article

Background: Genetic alterations in CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid neoplasms with CSF3R alterations. Patients (median age, 77 years) were categorized into groups with a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (n = 5), acute leukemia (n = 4), and other myeloid neoplasms (n = 4) based on the WHO 2022 and ICC criteria. Results: The CSF3R p.Thr618Ile mutation was most frequent (11/13), with additional pathogenic variants including p.Gln743Ter and frameshift mutations affecting the cytoplasmic tail. Variant allele frequencies (VAFs) ranged from 2% to 49%, with the highest median VAF in the MDS/MPN group. Co-mutations varied by subtype; MDS/MPN, NOS, and CMML cases frequently harbored mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SF3B1, SRSF2, ZRSR2), while acute leukemia cases showed alterations in JAK3, STAT3, and NRAS. Survival analysis revealed distinct patterns across the three diagnostic groups, with MDS/MPN having the poorest prognosis. Conclusion: This study expands the recognized spectrum of CSF3R-related myeloid neoplasms and highlights the clinical and molecular heterogeneity associated with these mutations, emphasizing the need for comprehensive molecular profiling and the potential for targeted therapies. Full article

Soy sauce (SS) is one of the most popular condiments in the world. However, Nε-carboxymethyl-lysine (CML) and 5-hydroxymethylfurfural (5-HMF), harmful Maillard reaction products, are present in SS. Worse still, their primary sources in SS production remain unclear, and their contents increase during the consumption of heated SS. In this study, CML and 5-HMF were simultaneously monitored, and thermal treatment and the addition of natural product were used to simultaneously reduce their contents during SS production and consumption. During SS production, CML and 5-HMF primarily originated from the raw materials used in SS production, Maillard reactions during fermentation, and the addition of food additives. Also, CML and 5-HMF were simultaneously found in commercial light soy sauce, dark soy sauce, and infant SS, and thermal treatment could increase their contents. Fortunately, additional thermal treatment of semi-finished SS (especially raw sauce and rude light SS) and appropriate concentrations of (−)-epicatechin (100 μM) and ascorbic acid (5 μM), respectively, added to SS for direct and heated consumption, could simultaneously reduce the CML and 5-HMF contents. This study highlights the presence of CML and 5-HMF in SS and proposes practical methods to simultaneously minimize their contents during production and consumption. Full article

The BCR-ABL1 chimeric oncoprotein plays a pivotal role in the pathogenesis of Chronic Myeloid Leukemia (CML) as its constitutive kinase activity transforms the hematopoietic stem cell, promoting pro-survival signaling. We and others have previously shown that the manipulation of BCR-ABL1 catalytic activity modulates its intracellular localization, thereby transforming the culprit of CML into a pro-apoptotic protein that selectively kills leukemic cells. Here, we investigated the role of the BCR coiled-coil and C2 domains on BCR-ABL1 intracellular localization and leukemogenic potential. We performed a bioinformatic analysis that identified two putative nuclear localization signals (NLSs) in BCR. Using recombinant DNA strategies, we generated multiple BCR and BCR-ABL1 mutants that were ectopically expressed in human cells. The intracellular localization of each construct was analyzed by immunofluorescence, while their biological activity was investigated employing proliferation and transforming assays. We show that BCR displays two nuclear localization signals functionally inactivated by the coiled-coil and C2 domains. The removal of these regions reactivated the nuclear migration of both BCR and BCR-ABL1 mutants. Moreover, BCR-ABL1 constructs devoid of the coiled-coil and C2 domains displayed reduced transforming potential in Ba/F3 cells and in primary human CD34+ progenitors. Finally, we demonstrate that the deletion of the C2 domain compromises TKI efficacy. Our findings identify two nuclear localization signals in the BCR sequence that are functionally suppressed by the coiled-coil and C2 domains. Targeting these regions may provide additional therapeutic strategies to manipulate both BCR-ABL1 intracellular localization and kinase activity. Full article

In this study, we selected the production processes and main products of three typical chemical enterprises in Shanghai, namely SH Petrochemical (part of the oil-refining sector), SK Ethylene, and HS Chlor-Alkali, to quantitatively assess the synergistic effects across technology, policy, and emission mechanisms. The localized air pollutant levels and greenhouse gas emissions of the three enterprises were calculated. The synergistic effects between the end-of-pipe emission reductions for air pollutants and greenhouse gas emissions were analyzed using the pollutant reduction synergistic and cross-elasticity coefficients, including technology comparisons (e.g., acrylonitrile gas incineration (AOGI) technology vs. traditional flare). Based on these data, we used the SimaPro software and the CML-IA model to conduct a life cycle environmental impact assessment regarding the production and upstream processes of their unit products. By combining the life cycle method and the scenario simulation method, we predicted the trends in the environmental impacts of the three chemical enterprises after the implementation of low-carbon development policies in the chemical industry in 2030. We also quantified the synergistic effects of localized air pollutant and greenhouse gas (GHG) emission reductions within the low-carbon development scenario by using cross-elasticity coefficients based on life cycle environmental impacts. The research results show that, for every ton of air pollutant reduced through end-of-pipe treatment measures, the HS Chlor-Alkali enterprise would increase its maximum CO₂ emissions, amounting to about 80 tons. For SK Ethylene, the synergistic coefficient for VOC reduction and CO₂ emissions when using AOGI thermal incineration technology is superior to that for traditional flare thermal incineration. The activities of the three enterprises had an impact on several environmental indicators, particularly the fossil fuel resource depletion potential, accounting for 69.48%, 53.94%, and 34.23% of their total environmental impact loads, respectively. The scenario simulations indicate that, in a low-carbon development scenario, the overall environmental impact loads of SH Petrochemical (refining sector), SK Ethylene, and HS Chlor-Alkali would decrease by 3~5%. This result suggests that optimizing the upstream power structure, using “green hydrogen” instead of “grey hydrogen” in hydrogenation units within refining enterprises, and reducing the consumption of electricity and steam in the production processes of ethylene and chlor-alkali are effective measures in reducing carbon emissions in the chemical industry. The quantification of the synergies based on life cycle environmental impacts revealed that there are relatively strong synergies for air pollutant and GHG emission reductions in the oil-refining industry, while the chlor-alkali industry has the weakest synergies. Full article

Background: N^ε-(carboxymethyl)-lysine (CML) is formed in the human body by non-enzymatically driven reactions including glycation, oxidation, and lipoxidation. CML is a ubiquitous product of normal physiology, but its levels are increased under disease conditions like chronic kidney disease (CKD) and diabetes mellitus (DM). Free CML is eliminated from the human body mainly through kidney excretion, and its accumulation in the kidney tissue is linked to CKD pathogenesis. Aim: The main goal of this study was to evaluate the relative contribution of CKD and Type 2 DM (T2DM) to the accumulation of CML in patients’ sera. Methods: The study included 22 patients with CKD without DM, 55 with CKD and comorbid T2DM, and 21 with T2DM without CKD. Serum CML levels were measured by ELISA. The Kruskal-Wallis test was used to detect differences among groups. Spearman correlation analysis was performed, and the one-tailed Dunn test was considered to indicate statistical significance at p < 0.05. Results: The median serum CML levels (CKD, 658.4 ± 434.3 ng/mL; CKD + T2DM, 431.3 ± 327.9 ng/mL; T2DM, 273.9 ± 134.2 ng/mL) differed significantly (p < 0.05) among the three patient groups. A positive correlation was observed between serum CML and microalbuminuria (p = 0.004; r = 0.58), proteinuria (p = 0.002; r = 0.6), and age (p = 0.007; r = 0.52) only in the CKD patients. In all T2DM patients, independent of CKD status, serum CML correlated negatively (p < 0.05) with postprandial glucose and duration of diabetes, while its correlation with fasting glucose and HbA1c was negative only in the T2DM cohort without CKD. Conclusions: In patients with CKD, higher levels of CML were observed compared to those with T2DM. Serum CML correlated positively with proteinuria, albuminuria, and patient age in non-diabetic CKD patients, and negatively with blood glucose, HbA1c, and DM duration of T2DM in patients without CKD. Full article

Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified miR-185 as a predictive biomarker where reduced expression in CD34⁺ treatment-naïve CML cells was associated with TKI resistance. We have also identified PAK6 as a target gene of miR-185 that was upregulated in CD34⁺ TKI-nonresponder cells. However, its role in regulating TKI resistance remains largely unknown. In this study, we specifically targeted PAK6 in imatinib (IM)-resistant cells and CD34⁺ stem/progenitor cells from IM-nonresponders using a lentiviral-mediated PAK6 knockdown strategy. Interestingly, the genetic and pharmacological suppression of PAK6 significantly reduced proliferation and increased apoptosis in TKI-resistant cells. Cell survivability was further diminished when IM was combined with PAK6 knockdown. Importantly, PAK6 inhibition in TKI-resistant cells induced cell cycle arrest in the G2-M phase and cellular senescence, accompanied by increased levels of DNA damage-associated senescence markers. Mechanically, we identified a PAK6-mediated MDM2-p21 axis that regulates cell cycle arrest and senescence. Thus, PAK6 plays a critical role in determining alternative cell fates in leukemic cells, and targeting PAK6 may offer a therapeutic strategy to selectively eradicate TKI-resistant cells. Full article

Precision medicine is transforming hematologic cancer care by tailoring treatments to individual patient profiles and moving beyond the traditional “one-size-fits-all” model. This review outlines foundational technologies, disease-specific advances, and emerging directions in precision hematology. The field is enabled by molecular profiling techniques, including next-generation sequencing (NGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), as well as epigenomic and proteomic analyses. Complementary tools such as liquid biopsy and minimal residual disease (MRD) monitoring have improved diagnosis, risk stratification, and therapeutic decision making. We discuss major molecular targets and personalized strategies across hematologic malignancies: FLT3 and IDH1/2 in acute myeloid leukemia (AML); Philadelphia chromosome–positive and Ph-like subtypes in acute lymphoblastic leukemia (ALL); BCR-ABL1 in chronic myeloid leukemia (CML); TP53 and IGHV mutations in chronic lymphocytic leukemia (CLL); molecular subtypes and immune targets in diffuse large B-cell lymphoma (DLBCL) and other lymphomas; and B-cell maturation antigen (BCMA) in multiple myeloma. Despite significant progress, challenges remain, including high costs, disparities in access, a lack of standardization, and integration barriers in clinical practice. However, advances in single-cell sequencing, spatial transcriptomics, drug repurposing, immunotherapies, pan-cancer trials, precision prevention, and AI-guided algorithms offer promising avenues to refine treatment and improve outcomes. Overcoming these barriers will be critical for ensuring the equitable and widespread implementation of precision medicine in routine hematologic oncology care. Full article

Artemisia annua L., the primary source of the antimalarial compound artemisinin, is of great importance for malaria treatment. However, its self-incompatibility (SI) restricts selfing breeding and results in unstable artemisinin content which is vulnerable to environmental fluctuations. To address this, our study employed fluorescence microscopy and transcriptomic analysis on stigmas post self- and cross-pollination to explore the molecular mechanisms of SI in Artemisia annua L. Fluorescence microscopy observations indicate that, three hours after pollination, cross-pollinated pollen tubes mostly exhibit normal filamentous growth, whereas the growth of self-pollinated pollen tubes is significantly inhibited, with most appearing as growth-arrested pollen tubes. Using transcriptome analysis, we generated approximately 25.03 GB of data assembled into 69,498 genes and identified 620 differentially expressed genes (DEGs), including 10 classified as SI response genes. Several specific SI-related candidate genes were identified, such as the S-locus receptor kinase (SRK), Calmodulin-like (CML), modifier (MOD), and exocyst complex component (EXO) genes, between AasB and AahA. These DEGs provide vital information for studying A. annua’s SI molecular mechanisms. The putative DEGs between the two groups provided important information for a further study of the molecular mechanisms of SI in A. annua. Candidate SI-associated genes are essential for the genetic engineering of A. annua to overcome SI and to avoid breeding inbred lines. Full article

To meet the growing demand for secure and reliable image protection in digital communication, this paper proposes a novel image encryption framework that addresses the challenges of high plaintext sensitivity, resistance to statistical attacks, and key security. The method combines a two-dimensional dynamically coupled map lattice (2D DCML) with elementary cellular automata (ECA) to construct a heterogeneous chaotic system with strong spatiotemporal complexity. To further enhance nonlinearity and diffusion, a multi-source perturbation mechanism and adaptive DNA encoding strategy are introduced. These components work together to obscure the image structure, pixel correlations, and histogram characteristics. By embedding spatial and temporal symmetry into the coupled lattice evolution and perturbation processes, the proposed method ensures a more uniform and balanced transformation of image data. Meanwhile, the method enhances the confusion and diffusion effects by utilizing the principle of symmetric perturbation, thereby improving the overall security of the system. Experimental evaluations on standard images demonstrate that the proposed scheme achieves high encryption quality in terms of histogram uniformity, information entropy, NPCR, UACI, and key sensitivity tests. It also shows strong resistance to chosen plaintext attacks, confirming its robustness for secure image transmission. Full article

This work shows an approach on the role of the gas mixture used in the pulsed DC plasma nitriding aiming to enhance the niobium cavitation erosion resistance through the formation of niobium nitride on the treated surfaces. For this purpose, nitriding was carried out at 1353 K (1080 °C) for 2 h, under a pressure of 1.2 kPa (9 Torr), and a 5 × 10⁻⁶ Nm³s⁻¹ (300 sccm) flow rate for three distinct gas mixtures, namely 30% N₂ + 50% H₂ + 20% Ar, 50% N₂ + 30% H₂ + 20% Ar, and 70% N₂ + 10% H₂ + 20% Ar. Surfaces were comparatively characterized before and after nitriding through scanning electron microscopy (SEM), X-ray diffractometry, 3D roughness, and nanoindentation hardness measurements. The cavitation erosion test was carried out in accordance with ASTM G32-09, obtaining the cumulative mass loss (CML) curve and the average (AER) and maximum (MER) erosion rate of the tested surfaces. Surfaces showed multiphase layers mainly constituted of ε-NbN and β-Nb₂N nitride phases, for the three distinct gas mixture conditions investigated. A CML of 25.0, 20.2, and 34.6 mg, and an AER of 1.56, 1.27, and 2.16 mg h⁻¹ was determined to the 960 min (16 h) cavitation erosion testing time, for NbN surfaces obtained at the 30% N₂, 50% N₂, and 70% N₂ gas mixture, respectively. In this case, the nominal incubation period (NIP) was 600, 650, 550 min, and the maximum erosion rate (MER) was 4.2, 3.4, and 5.1 mg h⁻¹, respectively. Finally, the enhancement of the cavitation erosion resistance, based on the NIP of the NbN surfaces, regarding the Nb substrates (with NIP of ≈100 min), was up ≈6 times, on average, thus significantly improving the cavitation erosion resistance of the niobium. Full article

In this study, the dominant pathogenic fungus of gray spot disease in loquat, which was isolated from postharvest decaying loquat fruits in Zhenjiang, was identified as Pestalotiopsis vismiae (P. vismiae) by morphological characteristics and DNA sequencing. At the same time, a strain of yeast E1, which could effectively inhibit the pathogen, was isolated from the loquat leaves and soil and identified as Metschnikowia pulcherrima (M. pulcherrima) by morphological and molecular biological characteristics. It significantly reduced the natural decay of loquat fruits without affecting fruit quality. Metschnikowia pulcherrima E1 (M. pulcherrima E1) exhibited significant biocontrol efficacy against P. vismiae, the causal agent of gray spot in loquat, reducing disease incidence to 22.73% compared to 100% in the control group. Transcriptome analysis revealed 1444 differentially expressed genes (DEGs) (1111 upregulated, 333 downregulated), with key genes (CML19, XTH23, GSTU10) validated by RT-qPCR. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted enrichment in plant–pathogen interactions, glutathione metabolism, and phenylpropanoid biosynthesis. These findings provided molecular insights into yeast-induced resistance, bridging biocontrol applications with mechanistic studies. Full article

When breastfeeding is not possible, infant formulas may be used instead of human milk. However, harmful advanced glycation end-products (AGEs) may be formed during thermal processing of infant formulas. The exposure to AGEs at such an early age can lead to chronic diseases in the future. Therefore, the aim of this study was to develop a sensitive method to determine the content of AGEs in infant formulas. Twenty commercial infant formulas (initial and follow-on) in liquid and powder form were investigated using liquid chromatography with tandem mass spectrometry (LC-MS/MS) with a multistep sample pretreatment procedure. Five selected glycation products were analyzed: N^ε-carboxyethyllysine (CEL), N^ε-carboxymethyllysine (CML), furosine, glyoxal lysine dimer (GOLD), and methylglyoxal lysine dimer (MOLD). The mean contents of the tested glycation products did not differ significantly between the initial and follow-on formulas. No significant differences were found in the concentrations of the analyzed compounds from different manufacturers. However, the liquid formulas contained significantly more CML. The estimated dietary exposure to the tested compounds was in the range of 42.5–92.6 μg/day, except for furosine (almost 2 mg/day). The developed method enabled the determination of selected AGEs in complex matrices such as infant formulas. Consumption of liquid infant formulas can result in higher exposure to some AGEs. Full article

Background: Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia (CML) often face adverse effects, prompting investigations into treatment-free remission (TFR) for patients with sustained deep responses. Methods: Our objective was to assess real-world outcomes of TFR in a single-center cohort of patients in the southeastern U.S., as well as to compare different TKI management strategies (abrupt cessation of a TKI at a standard dose, TKI dose tapering prior to cessation, or upfront TKI dose reduction followed by abrupt cessation before TFR). Results: We queried our CML database of 233 patients and identified 39 patients that aimed for TFR. The median TFR duration was 14.6 months, with 63% actively remaining in TFR with a median follow-up of 21 m. TFR was lost by 54%, 16%, 8%, and 21% of patients in 0–6 m, 6–12 m, 1–2 y, and >2 y, respectively. Among the three TKI management strategies, the safety outcomes were comparable, with no instances of disease progression or CML-related mortality. All patients who lost TFR successfully regained a major molecular response (MMR) upon the resumption of TKIs. In terms of efficacy, 61%, 59%, and 59% of patients who underwent abrupt cessation of standard-dose TKIs, standard-dose tapering, or upfront dose reduction maintained TFR, respectively. Conclusions: Our study highlights the relative safety of pursuing TFR via different TKI treatment strategies in a real-world setting. Full article

Helicobacter pylori (H. pylori) is regarded as a significant risk factor for gastritis, peptic ulcer disease, and gastric cancer. However, the increasing resistance of H. pylori strains has resulted in low eradication rates and ineffective treatments. Herein, we report on identification of a new quipazine derivative—compound 9c (N-(3-chlorobenzyl)-2-(piperazin-1-yl)quinolin-4-amine), which displayed antibacterial properties (MIC range 2–4 µg/mL) against H. pylori CagA-positive reference strains associated with an increased risk of gastric cancer, including metronidazole-resistant ATCC 43504, clarithromycin-resistant ATCC 700684 and susceptible J99 strain, as well as clinical, multidrug-resistant isolate (3CML, resistant to clarithromycin, metronidazole and levofloxacin). Compound 9c showed bacteriostatic activity (MBC/MIC ratio > 4), demonstrated antibiofilm-forming properties and prevented auto-aggregation of microbial cells. It also displayed an additive effect in ½ MIC (2 µg/mL) when administered with clarithromycin and/or metronidazole. Compound 9c had no impact on gut microbiota reference strains of S. aureus, E. coli, E. faecalis and L. paracasei as well as no hemolytic activity against sheep erythrocytes. Finally, by reducing the viability of the SNU-1 human gastric cancer cell line (IC₅₀ = 3.28 μg/mL), compound 9c might offer important implications regarding the oncogenic characteristics of cagA+ H. pylori strains. Full article