Search Results (295)

Background: Wide application of genome sequencing technologies has highlighted extensive genetic diversity in Acute Myeloid Leukemia (AML), yet the specific roles of individual genes remain unclear. This systematic review and meta-analysis aims to provide robust evidence for the prognostic impact of somatic gene mutations in de novo AML patients, while also exploring the prevalence of these mutations. Methods: Eligible studies were identified from PubMed and Scopus, with a focus on those reporting the prognostic influence of somatic gene mutations on overall survival (OS) or relapse-free survival (RFS) when compared to wild-type carriers. We calculated the pooled prevalence with 95% confidence intervals to assess the frequency of these mutations, and the pooled Hazard Ratio (HR) to compare OS and RFS associated with specific gene mutations. Results: We evaluated 53 somatic gene mutations using 80 studies, involving 20,048 de novo AML patients. The analysis revealed that the most prevalent affected genes were NPM1 (27%), DNMT3A (26%), and FLT3-ITD (24%). Mutations in CSF3R, TET2, and TP53 were significantly associated with poorer OS or RFS (p < 0.05). Sensitivity analysis confirmed that ASXL1, DNMT3A, and RUNX1 mutations were consistently linked to inferior OS or RFS. In contrast, CEBPAdm mutations were associated with favorable OS [HR = 0.39 (0.30–0.50)] and RFS [HR = 0.44 (0.37–0.54)]. Subgroup analysis showed that FLT3-ITD mutations were consistently associated with worse OS or RFS across all subgroups, though no significant subgroup differences were noted. No significant impact on OS or RFS was observed for mutations in GATA2, FLT3-TKD, KRAS, NRAS, IDH1, and IDH2. Conclusions: These findings provide critical insights into AML prognosis, aiding clinical decision-making and improving risk stratification strategies. Full article

Shearer drum cutting of coal seams generates over half of the coal dust in coal mines, while relevant studies focus more on micron-sized dust and much less on nano- to sub-micron-sized coal dust. Based on the self-developed experimental system for simulating dust generation from drum cutting of coal bodies, this study investigated the concentration distribution characteristics and physicochemical properties of 10 nm–10 μm coal dust generated from drum cutting of different rank coals with different cutting parameters. Results showed that the coal dust mass and number concentrations were concentrated in 2–10 μm and 10–200 nm, respectively, accounting for 90% of the total 10 nm–10 μm coal dust; the mass percentages of PM1/PM10 (PM1/PM10 = PM1 particles relative to PM10 particles, similarly hereinafter), PM1/PM2.5, and PM2.5/PM10 were 3.25–4.87%, 19.35–26.73%, and 14.82–18.81%, respectively, whereas over 99% of the total number of particles in the PM10 fraction are within the PM1 fraction (i.e., N-PM1/N-PM10 > 99%), that is, both N-PM1/N-PM2.5 and N-PM2.5/N-PM10 exceeded 99%. Lower-rank coal generates less 10 nm–10 μm coal dust, and either higher moisture content, firmness coefficient, or lower fixed carbon content of the coal can effectively reduce the 10 nm–10 μm coal dust generation. Either reduction in the tooth tip cone angle, the rotary speed, or increase in the mounting angle or the cutting depth can effectively inhibit the 10 nm–10 μm coal dust generation. Higher-rank coal dust shows fewer surface pores, smoother surfaces, larger contact angles, more hydrophobic groups, and fewer hydrophilic groups. The research results have filled the knowledge gap in the pollution characteristics of nano- to submicron-sized dust generated from shearer drum cutting of coal bodies, and can serve as an important reference for the development of dust reduction and suppression technologies in coal mining faces as well as the prevention of coal worker’s pneumoconiosis. Full article

The development of molecular profiling approaches for AML patients such as whole genome sequencing, whole exome sequencing and transcriptomic sequencing have greatly contributed to better understanding of leukemia development, progression and treatment responsiveness/resistance. These studies have generated a new knowledge about driver events operating in AML that can be translated into clinics, thus favoring the mutations; using this approach, more than 50% of older AML patients display molecular alterations, such as IDH1, IDH2, FLT3 (FLT3-TKD and FLT3-ITD), NPM1 and KMT2A rearrangements that can be targeted by specific drugs. Preclinical and clinical studies have supported the use of drugs targeting these molecular alterations as first-line therapy in association with induction chemotherapy in chemotherapy-fit patients or with a hypomethylating agent in association with a Bcl-2 inhibitor (Venetoclax) in chemotherapy-unfit patients. These studies have shown promising results that need to be confirmed through randomized clinical studies specifically involving the enrollment of older AML patients. Full article

Understanding the role of liquidity and leverage is crucial in assessing financial performance, particularly in the consumer goods sector. This study examined the impact of liquidity and leverage on financial performance, using a sample of 13 consumer goods firms listed on the Johannesburg Stock Exchange (JSE) from 2014 to 2024. Despite the present literature on this association, few traceable studies have investigated this phenomenon, and there is a dearth of literature in this sector. The dependent variable for this study was financial performance, and the return on assets (ROA) was employed as a proxy for financial performance. The independent variables employed for this study were liquidity (LIQ), leverage (LEV), and the quadratic term of leverage (LEV2). However, Net profit margin (NPM), inventory turnover (INVT), average collection period (ACP), firm size (FS), and its quadratic term (FS2) were the control variables. The researcher performed the Durbin–Wu–Hausman test, the Breusch–Pagan LM test, redundant fixed effect testing, the Hausman test, and the panel heteroskedasticity LR test before employing the suitable model. After employing the panel least squares (PLS), the fixed effects (FE) model was considered appropriate and efficient for this study. Applying the model, the researcher found a statistically significant and positive impact of LIQ, LEV2, NPM, and FS2 on ROA. Furthermore, a statistically significant and negative impact of ACP on ROA. However, the impact of LEV and FS was negative and statistically insignificant on ROA. Furthermore, the impact of INVT on ROA was statistically positive and insignificant. To improve the financial performance of the firms efficiently, this study recommends that financial managers of consumer goods firms should pay special attention to maintaining and monitoring a healthy liquidity ratio and implement sound working capital management. Furthermore, integrate the strategic liquidity planning into their financial decision-making. The findings highlight that while a moderate level of leverage might not increase financial performance, a strategic increase in debt to a certain optimal level can improve the financial performance of a firm. Full article

Acute Myeloid Leukemia (AML) is a genetically and clinically heterogeneous malignancy marked by poor prognosis and limited therapeutic options, especially in older patients. While conventional treatments such as the “7 + 3” chemotherapy regimen and allogeneic stem cell transplantation remain standard care options, the advent of next-generation sequencing (NGS) has transformed our understanding of AML’s molecular complexity. Among the emerging hallmarks of AML, metabolic reprogramming has gained increasing attention for its role in supporting leukemic cell proliferation, survival, and therapy resistance. Distinct AML subtypes—shaped by specific genetic alterations, including FLT3, NPM1, and IDH mutations—exhibit unique metabolic phenotypes that reflect their underlying molecular landscapes. Notably, FLT3-ITD mutations are associated with enhanced reactive oxygen species (ROS) production and altered energy metabolism, contributing to disease aggressiveness and poor clinical outcomes. This review highlights the interplay between metabolic plasticity and genetic heterogeneity in AML, with a particular focus on FLT3-driven metabolic rewiring. We discuss recent insights into how these metabolic dependencies may be exploited therapeutically, offering a rationale for the development of metabolism-targeted strategies in the treatment of FLT3-mutated AML. Full article

The dysregulation of m6A-related genes recognized as ‘writers’, ‘readers’, and ‘erasers’ is reported to be involved in the initiation, progression, and drug resistance of acute myeloid leukemia (AML). In the present study, we investigated the expression levels of various readers, writers, and erasers in pediatric AML patients. Additionally, we categorized the patients according to the molecular subtyping of common mutations and recurrent fusions and correlated the expression of m6A-associated genes with different molecular subtypes and evaluated their prognostic and clinical implications. A total of fifty-seven patients with pediatric de novo AML were enrolled in the study. The study cohort consisted of 41 males and 16 females with a median age of 7 years (range 1 to 12 years). A high expression of m6A RNA modification complex genes was noted in AML patients. Among the writers, METTL3 and METTL14 were found to be upregulated in 19 and 17 patients, the readers YTHDF1 and YTHDF2 showed higher expression in 6 and 10 patients, while a high expression of erasers FTO and ALKBH5 was found in 28 patients and 1 patient, respectively. Further, the expression of m6A regulators showed a significant association with genetic alterations including FLT3-ITD, RBM15::MKL fusions and NPM1 mutations. Additionally, while evaluating the prognostic implications, both the readers YTHDF1 and YTHDF2 showed a significant correlation with TLC at diagnosis (p < 0.05). Further, Kaplan–Meier estimation showed a poor event-free survival in cases with the overexpression of YTHDF1 (log-rank p = 0.028). Additionally, we noted a strong correlation between YTHDF1 overexpression and treatment-related mortality (log-rank p < 0.001), and a nearly significant correlation with YTHDF2 expression in such patients (log-rank p = 0.053) at a median follow-up of 8 months. Thus, our data suggest that m6A genes, especially readers YTHDF1 and YTHDF2, are involved in the disease prognosis of AML and probably function in an integrated manner with other m6A-modifying genes to subsequently play a role in AML pathogenesis. Full article

Background/Objectives: This study investigates genomic alterations (GA) between NPM1-mutated (NPM1mut) and wild-type (NPM1wt) acute myeloid leukemia (AML), aiming to better understand the AML genomic profile. NPM1mut AML represents a distinct clinical AML subtype with high relapse rates despite initial responsiveness to chemotherapy. Methods: A total of 4206 AML cases from 2019 to 2024 were analyzed using the FoundationOne Heme assay, incorporating comprehensive DNA and RNA sequencing. Patients were stratified into NPM1mut and NPM1wt cohorts, and genomic differences were systematically compared between the two groups. Results: Among 4206 cases, 633 (15.1%) featured NPM1 GA, with over 99% exhibiting short variant mutations. NPM1mut AML was more common in females (53.4% vs. 41.5%) and associated with a slightly higher median age (62 vs. 60 years). GA was more frequent in NPM1mut AML compared to the NPM1wt and included DNMT3A (39.2% vs. 12.6%; p < 0.0001), PTPN11 (18.3% vs. 7.5%; p < 0.0001), FLT3 (54.5% vs. 14.7%; p < 0.0001), IDH1 (16.1% vs. 5.6%; p < 0.0001), IDH2 (19.0% vs. 9.0%; p < 0.0001), TET2 (23.4% vs. 13.5%; p < 0.0001), and WT1 (12.5% vs. 9.4%; p = 0.02). GA was more frequent in NPM1wt AML and included ASXL1 (17.1% vs. 3.6%; p 0.0001), BCOR (7.5% vs. 1.6%; p < 0.0001), KMT2A (14.7% vs. 0.2%; p < 0.0001), RUNX1 (22.5% vs. 1.9%; p 0.0001), STAG2 (6.9% vs. 1.6%; p < 0.0001) and TP53 (19.1% vs. 4.1%; p < 0.0001). Conclusions: Mutations linked to therapy targets in AML, such as (FLT3 and IDH1/2), PTPN11, and DNMT3A (both associated with inferior outcomes), are more commonly observed in NPM1mut AML, whereas KMT2A, TP53, and myelodysplastic-related mutations are more commonly observed in NPM1wt AML. Full article

This study examines the intersection of environmental, social, and governance (ESG) disclosure (operationalized through sustainability reporting), corporate financial performance, and the behavioral dynamics of herding in capital structure decisions among non-financial firms in five ASEAN countries. As ESG and sustainability finance gain prominence in addressing climate change and climate risk, understanding the behavioral factors that relate to ESG adoption is crucial. Employing a quantitative approach, this research utilizes a purposive sample of 125 non-financial firms from Indonesia, Malaysia, the Philippines, Singapore, and Thailand, gathered from the Bloomberg Terminal spanning 2018–2023. Managerial Herding Ratio (MHR) is used to assess herding behavior, while Sustainability Report Disclosure Index (SRDI) measures ESG disclosure. Partial Least Squares Structural Equation Modeling (PLS-SEM) and Multigroup Analysis (MGA) were applied for data analysis. This research finds that while sustainability reporting enhances return on assets (ROA) and Tobin’s Q, it does not significantly relate to net profit margin (NPM). The findings also confirm that herding behavior—where companies mimic the financial structures of peers—moderates the relationship between sustainability reporting and performance outcomes, with leader firms gaining more from transparency efforts. This highlights the double-edged nature of herding: while it can accelerate ESG adoption, it may dilute the strategic depth of climate action if firms merely follow rather than lead. The study provides actionable insights for regulators and corporate strategists seeking to strengthen ESG finance as a driver for climate resilience and long-term stakeholder value. Full article

High-Temperature Proton-Exchange Membrane Fuel Cells (HT-PEMFCs) represent a promising clean energy technology and are valued for their fuel flexibility and simplified balance of plant. Their commercialization, however, is critically hindered by the prohibitive cost and resource scarcity of platinum-group metal (PGM) catalysts. The challenge is amplified in the phosphoric acid (PA) electrolyte of HT-PEMFCs, where the severe anion poisoning of PGM active sites necessitates impractically high catalyst loadings. This review addresses the urgent need for cost-effective alternatives by providing a comprehensive assessment of recent advancements in non-precious metal (NPM) catalysts for the oxygen reduction reaction (ORR) in HT-PEMFCs. It systematically explores synthesis strategies and structure–performance relationships for emerging catalyst classes, including transition metal compounds, metal–nitrogen–carbon (M-N-C) materials, and metal-free heteroatom-doped carbons. A significant focus is placed on M-N-C catalysts, particularly those with atomically dispersed Fe-Nx active sites, which have emerged as the most viable replacements for platinum due to their high intrinsic activity and notable tolerance to phosphate poisoning. This review critically analyzes key challenges that impede practical application, such as the trade-off between catalyst activity and stability, mass transport limitations in thick electrodes, and long-term degradation in the harsh PA environment. Finally, it outlines future research directions, emphasizing the need for a synergistic approach that integrates computational modeling with advanced operando characterization to guide the rational design of durable, high-performance catalysts and electrode architectures, thereby accelerating the path to commercial viability for HT-PEMFC technology. Full article

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