Search Results (286)

Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with NPM1 mutations (NPM1m) and KMT2A rearrangements (KMT2Ar) represent the primary targets of this emerging drug class. Acute myeloid leukemia (AML) with NPM1m—which accounts for approximately 30% of AML cases and AML or acute lymphoblastic leukemia (ALL) with KMT2Ar—and is present in 5–10% of cases, shares a common pathogenetic mechanism: the aberrant activation of the MEIS1–HOXA axis. These leukemic subsets are associated with poor prognosis, particularly in the relapsed/refractory (R/R) setting. For KMT2Ar AML, the prognosis is especially dismal, with a median overall survival (OS) of 2.4 months and a complete remission (CR) rate of only 5%. In NPM1m AML, intensive chemotherapy achieves remission in approximately 80% of cases, but relapse remains a major challenge, occurring in nearly 50% of patients. Relapsed NPM1m AML is linked to a poor prognosis, with a median OS of 6.1 months (12-month OS: 30%) and a median relapse-free survival (RFS) of 5.5 months (12-month RFS: 34%). Menin inhibitors directly target the leukemogenic transcriptional program driven by HOX and MEIS1, disrupting oncogenic signaling and offering a promising therapeutic approach for these high-risk patients. This class of agents has rapidly progressed through clinical development, showing promising antileukemic activity in both treatment-naïve and R/R AML. Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. In this review, we critically analyze the clinical development and therapeutic potential of the four most extensively studied menin inhibitors—revumenib, ziftomenib, bleximenib, and enzomenib. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options. Full article

A reliable estimation of protein requirements in lactating dairy cows is necessary for formulating nutritionally adequate diets, improving feed efficiency, and minimizing nitrogen excretion. This study aimed to develop machine learning-based models to predict net protein requirements for maintenance (NPm) and lactation (NPl) using random forest regression (RFR) and support vector regression (SVR). A total of 1779 observations were assembled from 436 peer-reviewed publications and open-access databases. Predictor variables included farm-ready variables such as milk yield, dry matter intake, days in milk, body weight, and dietary crude protein content. NPm was estimated based on the National Academies of Sciences, Engineering, and Medicine (NASEM, 2021) equations, while NPl was derived from milk true protein yield. The model adequacy was evaluated using 10-fold cross-validation. The RFR model demonstrated higher predictive performance than SVR for both NPm (R² = 0.82, RMSEP = 22.38 g/d, CCC = 0.89) and NPl (R² = 0.82, RMSEP = 95.17 g/d, CCC = 0.89), reflecting its capacity to model the rule-based nature of the NASEM equations. These findings suggest that RFR may provide a valuable approach for estimating protein requirements with fewer input variables. Further research should focus on validating these models under field conditions and exploring hybrid modeling frameworks that integrate mechanistic and machine learning approaches. Full article

Background/Objectives: Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations carries a poor prognosis. While FLT3 inhibitors like midostaurin show benefits in combination with chemotherapy, the role of allelic ratio (AR), NPM1 mutation status, and hematopoietic stem cell transplantation (HSCT) remains uncertain. Real-world data can help refine prognostic classification and treatment strategies. Methods: We retrospectively analyzed 37 fit patients with FLT3-ITD AML treated with standard “7+3” chemotherapy, with and without midostaurin, between 2013 and 2022. Patients were stratified by FLT3-ITD AR, NPM1 status, and treatment approach. Outcomes assessed included complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results: Overall, 67.6% achieved CR/CRi. Response rates did not differ significantly by AR (low vs. high: 66.7% vs. 69.2%) or midostaurin use (72.6% vs. 60%; p = 0.49). NPM1 mutations were associated with improved DFS (10.3 vs. 3 months, p = 0.036) but not OS. HSCT, performed in 54.1% of patients, mainly in first remission (CR1), significantly prolonged DFS (not reached vs. 5.3 months, p = 0.005) and remained an independent predictor in multivariate analysis (HR: 0.160, p = 0.039). OS (median 15.1 months) did not vary significantly across subgroups. Among patients achieving CR1, OS was significantly longer in those who underwent HSCT after midostaurin-based induction compared to those not transplanted (median OS not reached vs. 12.8 months; 95% CI, 6.9–18.7; p = 0.045), whereas no significant benefit was observed after standard induction. In a landmark analysis restricted to patients transplanted in CR1, those who had received midostaurin-based induction showed a trend toward improved OS compared to those treated with standard induction (median OS not reached vs. 11.5 months; 95% CI, 0.5–25.0; p = 0.086). Conclusions: This real-life study supports the importance of NPM1 mutations and HSCT in CR1, especially in the midostaurin era, for improving DFS in FLT3-ITD AML. These findings support updated guidelines for reducing the prognostic weight of AR and highlight the need for improved post-remission strategies in this setting. Full article

Background/Objectives: ALK+ Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma that is characterized by expression of the Anaplastic Lymphoma Kinase (ALK), which is induced by the t(2;5) chromosomal rearrangement, leading to the expression of the NPM-ALK fusion oncogene. Most previous preclinical models of ALK+ ALCL were based on overexpression of the NPM-ALK cDNA from heterologous promoters. Due to the enforced expression, this approach is prone to artifacts arising from synthetic overexpression, promoter competition and insertional variation. Methods: To improve the existing ALCL models and more closely recapitulate the oncogenic events in ALK+ ALCL, we employed CRISPR/Cas-based chromosomal engineering to selectively introduce translocations between the Npm1 and Alk gene loci in murine cells. Results: By inducing precise DNA cleavage at the syntenic loci on chromosome 11 and 17 in a murine IL-3-dependent Ba/F3 reporter cell line, we generated de novo Npm-Alk translocations in vivo, leading to IL-3-independent cell growth. To verify efficient recombination, we analyzed the expression of the NPM-ALK fusion protein in the recombined cells and could also show the t(11;17) in the IL-3 independent Ba/F3 cells. Subsequent functional testing of these cells using an Alk-inhibitor showed exquisite responsiveness towards Crizotinib, demonstrating strong dependence on the newly generated ALK fusion oncoprotein. Furthermore, a comparison of the gene expression pattern between Ba/F3 cells overexpressing the Npm-Alk cDNA with Ba/F3 cells transformed by CRISPR-mediated Npm-Alk translocation indicated that, while broadly overlapping, a set of pathways including the unfolded protein response pathway was increased in the Npm-Alk overexpression model, suggesting increased reactive changes induced by exogenous overexpression of Npm-Alk. Furthermore, we observed clustered expression changes in genes located in chromosomal regions close to the breakpoint in the new CRISPR-based model, indicating positional effects on gene expression mediated by the translocation event, which are not part of the older models. Conclusions: Thus, CRISPR-mediated recombination provides a novel and more faithful approach to model oncogenic translocations, which may lead to an improved understanding of the molecular pathogenesis of ALCL and enable more accurate therapeutic models of malignancies driven by oncogenic fusion proteins. Full article

Sarcomyxa edulis is a characteristic low-temperature, edible mushroom in Northeast China. It has a delicious taste and rich nutritional and medicinal value. S. edulis can undergo explosive fruiting, neat fruiting, and unified harvesting, making it suitable for factory production. The molecular mechanisms underlying fruiting body development in S. edulis remain poorly understood. This study employed transcriptome analysis to compare the post-ripening mycelium (NPM) and primordial fruiting bodies (PRMs) of the thermostable S. edulis strain PQ650759, which uniquely forms primordia under constant temperature. A total of 4862 differentially expressed genes (DEGs) (|log2(fold change)| ≥ 1) were identified and found to be predominantly enriched in biological processes such as cell wall organization, DNA replication, and carbohydrate metabolism. KEGG pathway analysis revealed significant enrichment in 20 metabolic pathways, including mismatch repair, yeast cell cycle, and starch/sucrose metabolism. Ten candidate genes (e.g., SKP1, MRE11, GPI) linked to cell cycle regulation, DNA repair, and energy metabolism were randomly selected and prioritized for functional analysis. Quantitative PCR validation confirmed the reliability of transcriptome data, with expression trends consistent across both methods. Our findings provide critical insights into the molecular regulation of fruiting body development in S. edulis and establish a foundation for future mechanistic studies and strain optimization in industrial cultivation. Full article

The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML); the gene, located in the nucleolus, codes for a protein that normally shuttles between the nucleus and the cytoplasm of the normal hematopoietic cells. Patients harboring NPM1 mutations are diagnosed as having NPM1-mutated AMLs, which are types of leukemia with distinct clinical and laboratory characteristics. The essential diagnostics for investigating NPM1-mutated AMLs, the interactions with concomitant mutations affecting prognosis and the therapeutic interventions that the treatment of such patients requires are discussed in this review. Novel investigational agents in current clinical trials are also highlighted, along with the roles of exportin 1 (XPO1), menin-KMT2A inhibitors and immunotherapy in NPM1-mutated AMLs. This review focuses on critically evaluating the available data and aims to reveal the secrets of NPM1-mutated AMLs. Full article

This study examined genetic diversity in the endangered medicinal plant Celastrus paniculatus using 62 individual samples from seven natural populations in northern and northeastern Thailand to inform conservation strategies. The analysis of the nuclear internal transcribed spacer (ITS) and ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (rbcL) markers revealed 17 haplotypes (CpI1–CpI17) across these populations, with 15 being population-specific. The genetic diversity varied significantly among populations: CMI showed the highest diversity (Hd = 0.944 ± 0.070), while LEI and LPN displayed complete homogeneity. The haplotype network identified a central shared haplotype (CpI4), suggesting a common ancestry, with the PLK population showing a distinct genetic divergence through unique haplotypes separated by multiple mutation steps. Genetic distance calculations revealed close relationships between LEI and NPM populations (distance = 0.0004), with greater differentiation between PLK and other populations (distances > 0.005). Phylogenetic analyses confirmed the species integrity while highlighting population clusters, especially PLK in ITS analyses and LPN in rbcL analyses. This genetic structure information provides a foundation for targeted conservation planning. Results suggest that conservation efforts should prioritize both genetically diverse populations (like CMI and MKM) and genetically distinct ones (like PLK) to preserve the maximum evolutionary potential. This study delivers crucial molecular data for developing evidence-based conservation strategies to protect this valuable medicinal species from further decline. Full article

Straw incorporation and manure are recognized as a sustainable farming practice to enhance soil fertility and improve crop yields. However, the effects of straw incorporation in combination with manure on productivity, soil nutrient status, N use efficiency (NUE), and the bacterial community are not well understood in wheat–summer maize rotation systems in the southern Shanxi Province. The five treatments were (1) CK, no fertilization; (2) NP, inorganic N and P fertilizers; (3) NPM, mineral N and P fertilizers plus chicken manure; (4) SNP, mineral N and P fertilizers plus maize straw; and (5) SNPM, mineral N and P fertilizers plus maize straw and chicken manure. The results showed that NP, NPM, SNP, and SNPM significantly increased wheat yields by 56.19%, 76.89%, 111.08%, and 114.30%, compared with CK, respectively. Nitrogen agronomic efficiency (AE_N), partial factor productivity (PEP_N), apparent recovery efficiency (Apparent RE_N), and accumulated recovery efficiency (Accumulated RE_N) increased by 103.36%, 37.19%, 76.39%, and 30.90% in the SNPM treatment, compared with NP. Straw incorporation and manure significantly improved soil fertility. Proteobacteria, Acidobacteriota, Actinobacteriota, Chloroflex, Bacteroidota, Planctomycetota, Gemmatimonadota, Armatimonadota, Firmicutes, Methylomirabilota, and Myxococcota were the predominant bacterial phyla. Compared with NP, straw incorporation and manure (NPM, SNP, and SNPM) decreased diversities (richness index, Chao1 index, and Shannon index). Principal coordinates (PCoA) and cluster analyses demonstrated that manure treatments (NPM and SNPM) significantly optimized bacterial community structure. Pearson’s correlation analysis demonstrated that organic matter, total phosphorus, available nitrogen, available phosphorus, and available potassium had significant positive correlations with Halanaerobiaeota but significant negative positive correlations with Chloroflexi, Entotheonellaeota, and Myxococcota. Wheat yields, AE_N, PEP_N, Apparent RE_N, and Accumulated RE_N were primarily and significantly negatively associated with Cyanobacteria. Straw incorporation in combination with manure significantly optimized bacterial community structure, wheat yields, and N use efficiency through improving soil fertility. Collectively, straw incorporation in combination with manure is a promising practice for sustainable development. Full article

Photovoltaic systems are increasingly recognized as one of the most advanced, efficient, and rapidly developing methods of electricity generation, utilizing the limitless potential of solar radiation while offering environmentally sustainable solutions to contemporary energy challenges. However, despite their clear benefits, issues such as high initial investment costs and relatively low energy efficiency must be carefully addressed during the design phase. Key considerations include the quantity and type of panels, battery capacity and number, environmental conditions, site-specific factors, and the mathematical models and interconnection strategies of system components. This study proposes a two-stage optimization approach for standalone photovoltaic systems, employing three distinct optimization algorithms—NSGA-II, DEMO, and Particle Swarm Optimization—to minimize both the Loss of Load Probability (LLP) and the life cycle cost (LCC). In the second stage, optimal solutions from the Pareto front are evaluated using three multi-criteria decision-making techniques: the hybrid AHP-TOPSIS method, VIKOR, and PROMETHEE. The proposed framework is applied to systems with storage batteries designed for deployment in three Cypriot cities, aiming to meet energy demands of 10, 15, and 20 kWh. The findings reveal a strong correlation between economic and energy performance and the degree of load coverage, with the combination of the DEMO algorithm and the AHP-TOPSIS method emerging as the most effective solution. Full article

Although 60% of AML patients respond well to standard chemotherapy, most patients eventually relapse, develop chemoresistance, and do not survive more than five years. Targeted therapies, including analogs of imiquimod belonging to the family of imiqualines, emerged as promising agents against AML. Notably, the first-generation imiqualine EAPB0503 proved selective potency against nucleophosmin-1-mutant (NPM1c) AML. Recently, chemical modifications of EAPB0503 led to the development of the lead compound from the second generation, EAPB02303. Here, we demonstrate that EAPB02303 displays 200-fold greater potency, broader activity across AML subtypes, and, importantly, a distinct mechanistic profile when compared to EAPB0503. Unlike EAPB0503, which primarily targeted NPM1c AML cells, EAPB02303 exhibits broad-spectrum activity across various AML subtypes. Remarkably, EAPB02303 anti-leukemic activity was attributed to the inhibition of PI3K/AKT/mTOR signaling activity. Nevertheless, NPM1c AML cells were more sensitive to EAPB02303, likely due to its ability to promote NPM1c protein degradation. In vivo, EAPB02303 potently reduced the leukemic burden and improved organ tumor infiltration in both wt-NPM1 and NPM1c AML xenograft mice. Yet, the significant prolonged survival was exclusive to NPM1c AML xenografts, likely due to superior response conferred by NPM1c degradation. Overall, these findings highlight the potential of EAPB02303 as a powerful therapeutic agent for a range of AML subtypes, supporting its further development for broader clinical use. Full article

The aluminum electrolysis industry faces significant challenges due to the high consumption and environmental impact of carbon anodes, which are prone to oxidation in high-temperature and strongly oxidizing environments. This study innovatively introduces aluminum fluoride (AlF₃) as an additive to enhance the oxidation resistance of carbon anodes for aluminum electrolysis. By systematically exploring microstructural evolution through SEM, XRD, Raman spectroscopy, and permeability analyses, it reveals that AlF₃ inserts fluorine atoms into carbon interlayers, forming F-C bonds that reduce interlayer spacing while promoting graphitization. Simultaneously, AlF₃-derived α-Al₂O₃ particles densify the anode and make it more compact, reaching the optimum when 7 wt.% AlF₃ is doped. The bulk density of the carbon anode increased to 2.08 g/cm³, porosity decreased to 0.315, and air permeability reached a minimum of 2.3 nPm. In addition, the fluorine intercalation reduces the electrical resistance to 2.12 Ω via conductive F-C clusters. The demonstrated efficacy of AlF₃ additives in enhancing the oxidation resistance and conductivity of carbon anodes suggests strong potential for industrial adoption, particularly in optimizing anode composition to reduce energy consumption. Full article

The standardization of multiparameter flow cytometry-based measurable residual disease (MFC-MRD) assessment in acute myeloid leukemia (AML) lacks clear criteria to define leukemia-associated immunophenotypes (LAIPs). In addition, the most specific/sensitive aberrations used to define LAIPs are often partially expressed by the leukemic clone at diagnosis, raising questions about their reliability for accurate MRD quantification. To address this, we investigated whether the quantification of LAIP+ cells reflects residual disease in cases of partial LAIP expression. The following two MFC-MRD approaches were evaluated by comparing their results to RT-qPCR for NPM1 mutations: (1) the LAIP-method, wherein all cells within the patient-specific template created at diagnosis are counted without further gating; (2) the LAIP-based different-from-normal (DfN)-method, wherein cells+ for LAIP-specific aberrant markers are further selected. A total of 125 bone marrow samples from 25 NPM1-mutated AML patients were studied. Our data demonstrate that the LAIP-based DfN-method improves the MFC-MRD accuracy and comparability with molecular MRD. ROC analysis identified cut-offs of 0.034% and 0.095% to discriminate positive/negative results in patients receiving intensive chemotherapy and hypomethylating agents, respectively. We also found distinct accuracy degrees based on the LAIP-specific aberrant markers used for MRD assessment. These results refine the MFC-MRD method and highlight the importance of therapy-specific MRD cut-offs and LAIP classification based on specificity and sensitivity. Full article

The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog (84) that displayed anti-cancer effects by inhibiting IKKβ, a key kinase in the NFκB pathway. Here, we present the synthesis of a regioisomer (51-106) and its characterization as a selective MAP3K1 inhibitor with improved metabolic stability and oral bioavailability. We used the small molecule MAP3K1 inhibitor in a proteomics study that identified NPM1 as a member of the MAP3K1 network. Full article

Background: In response to criticism and limitations of the Nutri-Score Nutrient Profiling Model (NS-NPM), the algorithm was updated in 2023. However, its impact on beverage classification remains partially assessed. Objective: This study aimed to compare the nutritional profiles of beverages marketed in Spain using the original and updated NS-NPM algorithms. Methods: Nutritional data for 3432 beverages in the “Drink Base” database were analyzed using both the 2015 (original) and 2023 (updated) NS-NPM versions. Results: The 2023 update showed significant changes compared to the 2015 version. Updated scores particularly increased for artificially sweetened beverages (+190.3%), milkshakes (+98.9%), nut-based beverages (+343.9%), cereal-based beverages (+651.3%), and the mix of plant-based beverages (+733%), leading to a less healthy classification. Conversely, scores decreased for fruit juices (−12.7%) and alcohol-substitute beverages (−8.2%), while legume-based beverages maintained their classification with minimal score variation (−1.4%), raising questions about the treatment of free sugars. The remaining beverage categories experienced score changes that did not alter their classification. Conclusions: The 2023 NS-NPM algorithm improves beverage classification by refining the differentiation of sugar-sweetened and artificially sweetened beverages, improving consumer guidance. While it increases discrimination, challenges remain in the classification of plant-based beverages and fruit juices. These findings highlight Nutri-Score’s impact on industry reformulation and its potential as a public health tool to promote healthier beverage choices. This study provides novel evidence on how the updated Nutri-Score algorithm may influence consumer perception and food policy in the Spanish context. Full article

Background: Wilms’ tumor gene 1 (WT1) is a critical player in acute myeloid leukemia (AML), often serving as a biomarker for measurable residual disease (MRD). The WT1 gene is overexpressed in the majority of AML cases at diagnosis, with apparently no correlation with prognosis, and in the meantime, its role in patients with low-level expression is still undefined. This study investigates the mutational landscape and clinical outcomes of AML patients with low WT1 expression at diagnosis. Methods: We analyzed 34 AML patients with low WT1 expression (WT1/ABL1 < 250) diagnosed and treated from 2013 to 2017 at three institutions. Next-generation sequencing (NGS) was employed to investigate the mutational status of 32 genes commonly mutated in AML. The presence of specific mutations, as well as clinical outcomes, was compared to the general AML population. Results: Patients with low WT1 expression showed a significantly higher mutational burden, with a median of 3.4 mutations per patient, compared to the general AML population. Notably, clonal hematopoiesis (CHIP) or myelodysplasia-related (MR) mutations, particularly in ASXL1, TET2, and SRSF2, were present in most patients with low WT1 expression. All but one case of NPM1- or FLT3-mutant AML in the low-WT1 cohort harbored more CHIP or MR mutations. Patients with low WT1 expression had an overall survival (OS) that was superimposable to the OS expected in MR AML. Conclusions: Low WT1 expression in AML is associated with a distinct and complex mutational profile, marked by frequent CHIP and MR mutations. Full article