Stellae-123 gene expression signature improved risk stratification in taiwanese acute myeloid leukemia patients.

The European Leukemia Net recommendations provide valuable guidance in treatment decisions of patients with acute myeloid leukemia (AML). However, the genetic complexity and heterogeneity of AML are not fully covered, notwithstanding that gene expression analysis is crucial in the risk stratification of AML. The Stellae-123 score, an AI-based model that captures gene expression patterns, has demonstrated robust survival predictions in AML patients across four western-population cohorts. This study aims to evaluate the applicability of Stellae-123 in a Taiwanese cohort. The Stellae-123 model was applied to 304 de novo AML patients diagnosed and treated at the National Taiwan University Hospital. We find that the pretrained (BeatAML-based) model achieved c-indexes of 0.631 and 0.632 for the prediction of overall survival (OS) and relapse-free survival (RFS), respectively. Model retraining within our cohort further improve the cross-validated c-indexes to 0.667 and 0.667 for OS and RFS prediction, respectively. Multivariable analysis identify both pretrained and retrained models as independent prognostic biomarkers. We further show that incorporating age, Stellae-123, and ELN classification remarkably improves risk stratification, revealing c-indices of 0.73 and 0.728 for OS and RFS, respectively. In summary, the Stellae-123 gene expression signature is a valuable prognostic tool for AML patients and model retraining can improve the accuracy and applicability of the model in different populations.

Unlocking the potential of biochar: an iron-phosphorus-based composite modified adsorbent for adsorption of Pb(II) and Cd(II) in aqueous environments and response surface optimization of adsorption conditions.

In this work, iron-phosphorus based composite biochar (FPBC) was prepared by modification with potassium phosphate and iron oxides for the removal of heavy metal ions from single and mixed heavy metal (Pb and Cd) solutions. FTIR and XPS characterization experiments showed that the novel modified biochar had a greater number of surface functional groups compared to the pristine biochar. The maximum adsorption capacities of FPBC for Pb(II) and Cd(II) were 211.66 mg·g-1 and 94.08 mg·g-1 at 293 K. The adsorption of Pb(II) and Cd(II) by FPBC followed the proposed two-step adsorption kinetic model and the Freundlich isothermal adsorption model, suggesting that the mechanism of adsorption of Pb(II) and Cd(II) by FPBC involved chemical adsorption of multiple layers. Mechanistic studies showed that the introduction of -PO4 and -PO3 chemisorbed with Pb(II) and Cd(II), and the introduction of -Fe-O increased the ion exchange with Pb(II) and Cd(II) during the adsorption process and produced precipitates such as Pb3Fe(PO4)3 and Cd5Fe2(P2O7)4. Additionally, the abundant -OH and -COOH groups also participated in the removal of Pb(II) and Cd(II). In addition, FPBC demonstrated strong selective adsorption of Pb(II) in mixed heavy metal solutions. The Response Surface Methodology(RSM) analysis determined the optimal adsorption conditions for FPBC as pH 5.31, temperature 26.01 °C, and Pb(II) concentration 306.30 mg·L-1 for Pb(II). Similarly, the optimal adsorption conditions for Cd(II) were found to be pH 5.66, temperature 39.34 °C, and Cd(II) concentration 267.68 mg·L-1. Therefore, FPBC has the potential for application as a composite-modified adsorbent for the adsorption of multiple heavy metal ions.

Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) and AXL tyrosine kinase receptor are known to be involved in the SARS-CoV-2 entry of the host cell. Therefore, targeting ACE2 and AXL should be an effective strategy to inhibit virus entry into cells. However, developing agents that can simultaneously target ACE2 and AXL remains a formidable task. The natural compound quercetin has been shown to inhibit AXL expression. MATERIALS AND METHODS: In this study, we employed PLGA nanoparticles to prepare nanoparticles encapsulated with quercetin, coated with ACE2-containing cell membranes, or encapsulated with quercetin and then coated with ACE-2-containing cell membranes. These nanoparticles were tested for their abilities to neutralize or inhibit viral infection. RESULTS: Our data showed that nanoparticles encapsulated with quercetin and then coated with ACE2-containing cell membrane inhibited the expression of AXL without causing cytotoxic activity. Nanoparticles incorporated with both quercetin and ACE2-containing cell membrane were found to be able to neutralize pseudo virus infection and were more effective than free quercetin and nanoparticles encapsulated with quercetin at inhibition of pseudo virus and SARS-CoV-2 infection. CONCLUSIONS: We have shown that the biomimetic nanoparticles incorporated with both ACE-2 membrane and quercetin showed the most antiviral activity and may be further explored for clinical application.

Exploring the impact of culture techniques and patient demographics on the success rate of primary culture of human periodontal ligament stem cells.

Background/purpose: Periodontal ligament stem cells (PDLSCs) have the potential for regenerating periodontal tissue. The study aims to investigate the impact of demographics (ages, gender, disease) and culture techniques (shipping storage time and culture method) on the success of primary culture. Materials and methods: PDLSCs were collected from 51 teeth of 26 patients and cultured via outgrowth (OG) and enzymatic digestion (ED) methods. Cells characteristics were confirmed by flow cytometry, MTT, and ARS. The primary culture success rate was evaluated with a serial chi-square test to determine the relationship with culture technique (ED/OG and ≤4 h/prolonged culture) and patient demographics (Young/Old, Female/Male, and Health/Periodontitis). Results: The overall success rate of Health group (69.7%) was higher than Periodontitis (38.9%). Culturing within 4 h possessed a higher success rate (71.8%) than prolonged group (16.7%) regardless of patient demographics, and using OG method (81.5%) revealed more promising. Subgroup analysis of 39 cases (culture within 4 h) found that the success rate of OG was higher than ED in the Old group (87.5%-25.0%) and in the Periodontitis group (83.3%-25.0%). Conclusion: Primary culturing of PDLSCs within 4 h and using the outgrowth method led to higher success rates regardless of patient demographics. It can achieve successful PDLSCs culture of older patients or patients with periodontal disease by appropriate culture technique.

In CKD, empagliflozin reduced kidney disease progression at a median 2 y, regardless of primary kidney disease type.

SOURCE CITATION: EMPA-KIDNEY Collaborative Group. Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024;12:51-60. 38061372.

Use of Reverse Shock Index Multiplied by Simplified Motor Score in a Five-Level Triage System: Identifying Trauma in Adult Patients at a High Risk of Mortality.

Background and Objectives: The Taiwan Triage and Acuity Scale (TTAS) is reliable for triaging patients in emergency departments in Taiwan; however, most triage decisions are still based on chief complaints. The reverse-shock index (SI) multiplied by the simplified motor score (rSI-sMS) is a more comprehensive approach to triage that combines the SI and a modified consciousness assessment. We investigated the combination of the TTAS and rSI-sMS for triage compared with either parameter alone as well as the SI and modified SI. Materials and Methods: We analyzed 13,144 patients with trauma from the Taipei Tzu Chi Trauma Database. We investigated the prioritization performance of the TTAS, rSI-sMS, and their combination. A subgroup analysis was performed to evaluate the trends in all clinical outcomes for different rSI-sMS values. The sensitivity and specificity of rSI-sMS were investigated at a cutoff value of 4 (based on previous study and the highest score of the Youden Index) in predicting injury severity clinical outcomes under the TTAS system were also investigated. Results: Compared with patients in triage level III, those in triage levels I and II had higher odds ratios for major injury (as indicated by revised trauma score < 7 and injury severity score [ISS] ≥ 16), intensive care unit (ICU) admission, prolonged ICU stay (≥14 days), prolonged hospital stay (≥30 days), and mortality. In all three triage levels, the rSI-sMS < 4 group had severe injury and worse outcomes than the rSI-sMS ≥ 4 group. The TTAS and rSI-sMS had higher area under the receiver operating characteristic curves (AUROCs) for mortality, ICU admission, prolonged ICU stay, and prolonged hospital stay than the SI and modified SI. The combination of the TTAS and rSI-sMS had the highest AUROC for all clinical outcomes. The prediction performance of rSI-sMS < 4 for major injury (ISS ≥ 16) exhibited 81.49% specificity in triage levels I and II and 87.6% specificity in triage level III. The specificity for mortality was 79.2% in triage levels I and II and 87.4% in triage level III. Conclusions: The combination of rSI-sMS and the TTAS yielded superior prioritization performance to TTAS alone. The integration of rSI-sMS and TTAS effectively enhances the efficiency and accuracy of identifying trauma patients at a high risk of mortality.

Mechanism behind the Controlled Generation of Liquid Metal Nanoparticles by Mechanical Agitation.

The size-controlled synthesis of liquid metal nanoparticles is necessary in a variety of applications. Sonication is a common method for breaking down bulk liquid metals into small particles, yet the influence of critical factors such as liquid metal composition has remained elusive. Our study employs high-speed imaging to unravel the mechanism of liquid metal particle formation during mechanical agitation. Gallium-based liquid metals, with and without secondary metals of bismuth, indium, and tin, are analyzed to observe the effect of cavitation and surface eruption during sonication and particle release. The impact of the secondary metal inclusion is investigated on liquid metals' surface tension, solution turbidity, and size distribution of the generated particles. Our work evidences that there is an inverse relationship between the surface tension and the ability of liquid metals to be broken down by sonication. We show that even for 0.22 at. % of bismuth in gallium, the surface tension is significantly decreased from 558 to 417 mN/m (measured in Milli-Q water), resulting in an enhanced particle generation rate: 3.6 times increase in turbidity and ∼43% reduction in the size of particles for bismuth in gallium liquid alloy compared to liquid gallium for the same sonication duration. The effect of particles' size on the photocatalysis of the annealed particles is also presented to show the applicability of the process in a proof-of-concept demonstration. This work contributes to a broader understanding of the synthesis of nanoparticles, with controlled size and characteristics, via mechanical agitation of liquid metals for diverse applications.

Potassium Chloride as an Effective Alternative to Sodium Chloride in Delaying the Thermal Aggregation of Liquid Whole Egg.

The potential of potassium chloride (KCl) to be used as a substitute for sodium chloride (NaCl) was studied by monitoring the effects of salt treatment on thermal behavior, aggregation kinetics, rheological properties, and protein conformational changes. The results show that the addition of KCl can improve solubility, reduce turbidity and particle size, and positively influence rheological parameters such as apparent viscosity, consistency coefficient (K value), and fluidity index (n). These changes indicate delayed thermal denaturation. In addition, KCl decreased the content of ß-sheet and random coil structures and increased the content of α-helix and ß-turn structures. The optimal results were obtained with 2% KCl addition, leading to an increase in Tp up to 85.09 °C. The correlation results showed that Tp was positively correlated with solubility, α-helix and ß-turn but negatively correlated with ΔH, turbidity, ß-sheet and random coil. Overall, compared to NaCl, 2% KCl is more effective in delaying the thermal aggregation of LWE, and these findings lay a solid theoretical foundation for the study of sodium substitutes in heat-resistant liquid egg products.

Large Language Model Performance on Practice Epilepsy Board Examinations.

This diagnostic study examines whether large language models are able to pass practice licensing examinations for epilepsy.

Curcumin regulates pulmonary extracellular matrix remodeling and mitochondrial function to attenuate pulmonary fibrosis by regulating the miR-29a-3p/DNMT3A axis.

Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5 mg/kg) and treated with CCM (25 mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff-Van Gieson, Picro sirius red, and Masson's trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.

Kinome expression profiling improves risk stratification and therapeutic targeting in myelodysplastic syndromes.

The human kinome, which comprises over five hundred kinases, plays a critical role in regulating numerous essential cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in myelodysplastic syndrome (MDS) have not been systematically investigated. In this study, we evaluated the kinome expression profiles of 341 adult patients with primary MDS and identified seven kinases (PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, and PRKCZ) whose expression levels were highly predictive of compromised patient survival. We then constructed the KInase Stratification Score (KISS) by combining the weighted expressions of the seven kinases, and validated its prognostic significance in two external MDS cohorts. A higher KISS was associated with older age, higher peripheral blood and marrow blast percentages, higher Revised International Prognostic Scoring System (IPSS-R) risks, complex karyotype, and mutations in several adverse-risk genes in MDS, such as ASXL1, EZH2, NPM1, RUNX1, STAG2, and TP53. Multivariate analysis confirmed that a higher KISS was an independent unfavorable risk factor in MDS. Mechanistically, the KISS-high patients were enriched for genesets associated with hematopoietic and leukemic stem cell signatures. By investigating the Genomics of Drug Sensitivity in Cancer (GDSC) database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.

Chromosome-level genome assembly provides insights into the genome evolution and functional importance of the phenylpropanoid-flavonoid pathway in Thymus mongolicus.

BACKGROUND: Thymus mongolicus (family Lamiaceae) is a Thyme subshrub with strong aroma and remarkable environmental adaptability. Limited genomic information limits the use of this plant. RESULTS: Chromosome-level 605.2 Mb genome of T. mongolicus was generated, with 96.28% anchored to 12 pseudochromosomes. The repetitive sequences were dominant, accounting for 70.98%, and 32,593 protein-coding genes were predicted. Synteny analysis revealed that Lamiaceae species generally underwent two rounds of whole genome duplication; moreover, species-specific genome duplication was identified. A recent LTR retrotransposon burst and tandem duplication might play important roles in the formation of the Thymus genome. Using comparative genomic analysis, phylogenetic tree of seven Lamiaceae species was constructed, which revealed that Thyme plants evolved recently in the family. Under the phylogenetic framework, we performed functional enrichment analysis of the genes on nodes that contained the most gene duplication events (> 50% support) and of relevant significant expanded gene families. These genes were highly associated with environmental adaptation and biosynthesis of secondary metabolites. Combined transcriptome and metabolome analyses revealed that Peroxidases, Hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferases, and 4-coumarate-CoA ligases genes were the essential regulators of the phenylpropanoid-flavonoid pathway. Their catalytic products (e.g., apigenin, naringenin chalcone, and several apigenin-related compounds) might be responsible for the environmental tolerance and aromatic properties of T. mongolicus. CONCLUSION: This study enhanced the understanding of the genomic evolution of T. mongolicus, enabling further exploration of its unique traits and applications, and contributed to the understanding of Lamiaceae genomics and evolutionary biology.

The impact of icodextrin on the outcomes of incident peritoneal dialysis patients.

OBJECTIVE: The aim of the study is to investigate the effects of icodextrin on the risks of death, technique failure and the first episode of peritonitis in peritoneal dialysis (PD) patients. METHODS: From medical records of a medical center in Taiwan, a total of 725 newly diagnosed end-stage kidney disease patients receiving PD for at least 90 days from January 1, 2007 to December 31, 2018 were identified. These patients were grouped as 190 icodextrin users and 535 non-users. Users were defined as utilization of icodextrin for ≥ 50% of their PD duration. The use of icodextrin was considered a time-varying exposure in the Cox proportional hazard model. The risks of death, technique failure and the first episode of peritonitis were compared between two cohorts by the end of 2018. RESULTS: Compared to the non-users, the icodextrin users had significant lower risks of mortality (6.5 vs.7.2 per 100 person-years; adjusted HR = 0.62, 95% CI = 0.42-0.91) and technique failure (12.7 vs. 15.2 per 100 person-years; adjusted HR = 0.61, 95% CI = 0.47-0.81), and the first peritonitis episode (5.0 vs. 17.0 per 100 person-years; adjusted HR = 0.22, 95% CI = 0.14-0.35). The risk of peritonitis reduced further in icodextrin users with diabetes and with cardiovascular disease. CONCLUSION: Icodextrin was associated with lower risks of mortality, technique failure, and the first episode of peritonitis.

Clinical dose rationale of tislelizumab in patients with solid or hematological advanced tumors.

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune-mediated AEs, and infusion-related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure-response (E-R) analyses by logistic regression using data from study BGB-A317-001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018-2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E-R relationship. Overall, the totality of data, including efficacy, safety, and E-R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.

Dachshund Homolog 1: Unveiling Its Potential Role in Megakaryopoiesis and Bacillus anthracis Lethal Toxin-Induced Thrombocytopenia.

Lethal toxin (LT) is the critical virulence factor of Bacillus anthracis, the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression. Through cDNA microarray analysis, we identified Dachshund homolog 1 (DACH1) as a gene that was upregulated upon TPA treatment but downregulated in the presence of TPA and LT, purified from the culture supernatants of B. anthracis. To investigate the function of DACH1 in megakaryocytic differentiation, we employed short hairpin RNA technology to knock down DACH1 expression in HEL cells and assessed its effect on differentiation. Our data revealed that the knockdown of DACH1 expression suppressed megakaryocytic differentiation, particularly in polyploidization. We demonstrated that one mechanism by which B. anthracis LT induces suppression of polyploidization in HEL cells is through the cleavage of MEK1/2. This cleavage results in the downregulation of the ERK signaling pathway, thereby suppressing DACH1 gene expression and inhibiting polyploidization. Additionally, we found that known megakaryopoiesis-related genes, such as FOSB, ZFP36L1, RUNX1, FLI1, AHR, and GFI1B genes may be positively regulated by DACH1. Furthermore, we observed an upregulation of DACH1 during in vitro differentiation of CD34-megakaryocytes and downregulation of DACH1 in patients with thrombocytopenia. In summary, our findings shed light on one of the molecular mechanisms behind LT-induced thrombocytopenia and unveil a previously unknown role for DACH1 in megakaryopoiesis.

Effects of freezing on the gelation behaviors of liquid egg yolks affected by saccharides: thermal behaviors and rheological and structural changes.

Monitoring and controlling the freezing process and thermal properties of foods is an important means to understand and maintain product quality. Saccharides were used in this study to regulate the gelation of liquid egg yolks induced by freeze‒thawing; the selected saccharides included sucrose, L-arabinose, xylitol, trehalose, D-cellobiose, and xylooligosaccharides. The regulatory effects of saccharides on frozen egg yolks were investigated by characterizing their thermal and rheological properties and structural changes. The results showed that L-arabinose and xylitol were effective gelation regulators. After freeze‒thawing, the sugared egg yolks exhibited a lower consistency index and fewer rheological units than those without saccharides, indicating controlled gelation. Weaker aggregation of egg yolk proteins was confirmed by smaller aggregates observed by confocal laser scanning microscopy and smaller particle sizes. Saccharides alleviated the freeze-induced conversion of α-helices to ß-sheets in egg yolk proteins, exposing fewer Trp residues. Overall, L-arabinose showed the greatest improvement in regulating the gelation of egg yolks, followed by xylitol, which is correlated with its low molecular weight.

Testing adulterated liquid-egg: developing rapid detection techniques based on colorimetry, electrochemistry, and interfacial fingerprinting.

To develop rapid detection techniques for liquid eggs' adulteration, three types of adulterations were considered: water dilution, manipulation of yolk ratio in whole egg, and blending different varieties of egg white or yolk. Objective: Establish detection techniques utilizing colorimetry, electrochemistry, and interfacial fingerprinting for these adulterations, respectively. Results: Colorimetry allows for detection (1 min·sample-1) of water dilution through linear (R2 ≥ 0.984) and exponential fitting (R2 ≥ 0.992); Electrochemistry enables detection (6 min·sample-1, R2 ≥ 0.979) of the adulteration of yolk ratio in whole egg; Interfacial fingerprinting technique effectively detects (detection duration: 10 min·sample-1, detection limit: 1.0-10.0 wt%) the adulteration of different varieties of egg white. Subsequently, through 3D-fluorescence microscopy (interface height variation: 22.49-573.45 µm), interfacial tension variation (65.54-35.48 mN·m-1), contact angle variation (89.7°-32.9°), particle size range (free water: 0.94-14.29 µm; protein aggregation: 6.57-10.76 µm), and etc., interfacial fingerprinting mechanism was elucidated. This research contributes novel insights into the detection of adulteration in liquid eggs.

Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis. PREDICTORS: Measurement of 448 known plasma metabolites. OUTCOMES: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument. ANALYTICAL APPROACH: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant." RESULTS: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m2, with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models. LIMITATIONS: Lack of a second independent cohort for external validation of our findings. CONCLUSIONS: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed. PLAIN-LANGUAGE SUMMARY: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD.

Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.

Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPAbZIP-inf) is classified within the favorable-risk group by the 2022 European LeukemiaNet (ELN-2022). However, heterogeneous clinical outcomes are still observed in these patients. In this study, we aimed to investigate the mutation profiles and transcriptomic patterns associated with poor outcomes in patients with CEBPAbZIP-inf. One hundred and thirteen CEBPAbZIP-inf patients were identified in a cohort of 887 AML patients homogeneously treated with intensive chemotherapy. Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf. RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS). CEBPAbZIP-inf patients with a shorter EFS had higher expression of IFN-stimulated genes (IRF2, IRF5, OAS2, and IFI35). Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival, and the results were independently validated in the TARGET AML cohort. In conclusion, concurrent WT1 or DNMT3A mutations and a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPAbZIP-inf, and upfront allogeneic transplantation may be indicated for better long-term disease control.