Browse Articles
Discover research articles across all indexed journals
Comprehensive molecular and functional analysis of <i>NUTM1</i> -rearranged leukemia
Abstract NUTM1 rearrangement defines a significant subset of B-cell acute lymphoblastic leukemia (B-ALL), particularly in infants lacking KMT2A rearrangements, yet its underlying molecular characteristics remain poorly understood. Here, we establish that NUTM1-rearranged (NUTM1-r) leukemia is a discrete entity characterized by a unique transcriptional and epigenetic landscape, notably featuring global DNA hypomethylation, irrespective of the 5′ fusion partner. Functional interrogation of NUTM1 fusions reveals a dual oncogenic role: they drive commitment toward the B-lymphoid lineage while concurrently conferring potent leukemic stem cell properties. Strikingly, expression of a representative fusion, BRD9-NUTM1, is sufficient to induce serially transplantable B-cell progenitor, prepro–B-like leukemia in vivo, faithfully recapitulating the key molecular and immunophenotypic features of human NUTM1-r B-ALL. Mechanistically, NUTM1 fusions establish an aberrant chromatin state, marked by global enhancement of H3K27 acetylation and the creation of distinctive open chromatin regions that co-opt both B-lineage and stemness-related transcriptional programs, including those involving NF-κB and posterior HoxA genes. In stark contrast to resistant KMT2A-rearranged leukemias, NUTM1-r leukemic cells exhibit a profound sensitivity to chemotherapy. This vulnerability is mechanistically linked to the leukemia's dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, revealing specific vulnerabilities that rationalize their favorable clinical outcomes and suggest opportunities for modified therapeutic strategies.
Interferon-induced protein 35 (IFI35) is associated with COVID-19 severity and clinical outcomes
Ceramide disrupts TM9SF2-PGK1 axis to redirect PD-L1 trafficking and enhance antitumor immunity
Time to revise myeloma diagnostic criteria? A decade of accumulated evidence on a serum free light chain ratio of ≥100
Abstract In 2014, the International Myeloma Working Group (IMWG) expanded multiple myeloma diagnostic criteria to include a serum free light chain (sFLC) ratio of ≥100 as a standalone myeloma-defining biomarker, based on studies suggesting ∼80% risk of progression to overt myeloma at 2 years. However, subsequent studies demonstrate a substantially lower risk of progression, with population-based registry data showing a 2-year risk as low as 30.4% in this group. Importantly, subsequent data showed that &gt;70% of patients with an sFLC ratio ≥100 have 24-hour monoclonal proteinuria &lt;200 mg, a subgroup with particularly low progression risk (13.5% at 2 years) and minimal risk of irreversible renal failure. Furthermore, with the IMWG diagnostic amendment, an sFLC ratio ≥100 is currently included within the composite end point of progression-free survival in early-intervention clinical trials of high-risk smoldering multiple myeloma (SMM), which poses a risk of misclassifying biochemical changes as clinically meaningful events. We propose immediate revision of the diagnostic criteria to remove sFLC ratio ≥100 as a standalone myeloma-defining event and exclusion of patients with an sFLC ratio ≥100 from trials of newly diagnosed myeloma. These patients should be included in prospective studies on therapeutic interventions in high-risk SMM as well as active surveillance with modern imaging to define their natural history in the contemporary era.
Clonidine protects rat hippocampal and cortical neurons from oxygen-glucose deprivation and reoxygenation-induced injury through HCN Channels
Extending the mean-field microkinetics for an accurate and efficient modeling of complex heterogeneous catalyst surfaces
Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial
Abstract Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic-phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from the ASC4FIRST trial, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years' median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4% [95% confidence interval (CI), 13.6-31.3]; 1-sided P&lt; .001) and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7% [95% CI, 17.6-41.8]; 1-sided P&lt; .001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1% [95% CI, 2.3-28.0]; 1-sided P&lt; .05), suggesting possible clinical benefit, although the study was not designed to formally confirm statistical significance for this secondary end point. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5%; 46.5%), imatinib (23.2%; 47.5%), and 2G TKIs (54.9%; 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215-0.997). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP. This trial was registered at www.clinicaltrials.gov as NCT04971226.
On economic and environmental effects of expanding PV deployment in Poland
Anatomy of a post-subduction collision
Abstract The spatiotemporal interplay of long-lasting post-orogenic deformations make continental collision zones among Earth’s most enigmatic systems. Here, we employ three-dimensional thermomechanical modeling to decode mantle dynamics of the Arabian-Eurasian collision—an archetype of post-subduction tectonics. Our key findings reveal that plumelet-plate interactions drive deformation both within and at the margins of convergent plates, forming modern kinematics, surface tectonics, and plate boundary configurations. We document previously unrecognized segmentation of the subducted Neotethyan slabs (Bitlis and Zagros) accompanied by upper-plate tearing, which fundamentally modifies the seismotectonic stress accumulation along the Arabian-Turkish-Iranian boundary. The convective support from the plumelet beneath the former Tethyan magmatic arc drives drip-like lithospheric removal under the southern Georgian highland, providing a regional-scale example of arc-to-intraplate deformation transformation. Our results offer a unified framework for understanding how upper mantle processes control surface deformation in post-subduction systems dominated by plumelet dynamics.
Benchmarking clonal hematopoiesis in sickle cell disease
Clinically significant prostate cancer detection with deep learning in a multi-center magnetic resonance imaging study
DNA affects the phenotype of fuel-dependent coacervate droplets
Abstract Synthetic cells emulate fundamental biological behaviors, like growth, metabolism, and mobility, but have lacked genotype-driven selection, which is essential for Darwinian evolution. Here, we introduce libraries of short DNA sequences as genotypes into fuel-dependent peptide-RNA-based coacervate droplets, serving as synthetic cells. By sequencing, we identify sequences that partition in the droplets, revealing strong preferences for guanine-rich and adenine-rich motifs. These sequences affect the synthetic cell phenotype—adenine-rich sequences shorten droplet lifetimes through hybridization. In contrast, guanine-rich sequences kinetically trap droplets via peptide interactions, altering dissolution rates and morphology. This study demonstrates how genotype affects phenotype in synthetic cells, establishing essential design principles for achieving Darwinian evolution in minimal protocellular systems.
Ketones and the NLRP3 inflammasome: you are what you eat
Diagnostic validation of the Chinese version of the five-part questionnaire for screening joint hypermobility in young adults
Abstract Joint hypermobility shows considerable variability across populations, yet validated screening tools for Mandarin-speaking cohorts are lacking. The Five-Part Questionnaire (5PQ) is widely used internationally, but its properties have not been evaluated in Chinese populations. This study assessed the validity and reliability of the Chinese version of the 5PQ (5PQ-CN) in a cohort of young Chinese university students. Participants completed the 5PQ-CN and underwent clinician-administered Beighton Score (BS) assessment, using the internationally recommended cut off of ≥ 5 to identify generalised joint hypermobility (GJH). Diagnostic validity was examined using sensitivity, specificity, predictive values, accuracy, and the area under the receiver operating characteristic curve (AUC). Test-retest reliability was evaluated using Cohen’s kappa (κ) and intraclass correlation coefficients (ICC). A total of 1,910 participants were recruited; 615 were included in the validity analysis and 325 in the reliability subgroup. The 5PQ-CN showed 78.6% sensitivity, 65.8% specificity, 72.2% accuracy, and an AUC of 0.722. Test-retest reliability demonstrated substantial agreement (κ = 0.703) and moderate consistency for the total score (ICC = 0.707). The 5PQ-CN is a valid and reliable self-report instrument for screening GJH in young Chinese adults within a university setting. Its high feasibility and sensitivity make it a useful complement to clinician-based assessments, particularly in large-scale or resource-limited epidemiological settings.
Deformation- and damage-free transfer of soft electronics onto highly curved and fragile biological surfaces
Abstract Seamless integration of soft electronics with biological tissues enables high-fidelity physiological sensing by maintaining intimate mechanical and thermal contact. However, transferring these devices onto highly curved and fragile surfaces remains challenging, as conventional methods often induce strain, thermal distortion, or tissue damage. To address these challenges, we introduce a deformation-decoupling, adhesion-switchable yield-stress fluid (DAYS-fluid) that enables non-invasive, damage-free transfer of soft electronics onto complex biological surfaces, including those with undercuts and negative curvature. DAYS-fluid undergoes a reversible solid-to-liquid transition at an ultra-low yield stress of 0.0253 kPa, far below the rupture pressure (~0.2 kPa) of extremely fragile biological substrates such as raw egg yolk. This low yield stress, combined with tunable viscosity, decouples fluid motion from embedded electronics, preserving structural integrity during transfer. A water-triggered adhesion-switching mechanism further reduces interfacial adhesion to near zero, enabling gentle detachment. We demonstrate high-fidelity thermal sensing on moving joints, without compromising device performance or tissue integrity.
Increased prevalence of clonal hematopoiesis in children with sickle cell disease
Abstract Recent studies have reached opposing conclusions about whether clonal hematopoiesis (CH) is increased or decreased in patients with sickle cell disease (SCD). Given that CH is typically age-related, its presence in children with SCD could offer unique insights into early-life mutagenesis and disease-related stressors. We tested the primary and secondary hypotheses that children with SCD would have a higher prevalence of CH than age-, sex-, and race-matched children without SCD and that children with hydroxyurea would have a higher CH prevalence than children not treated with hydroxyurea. To address this, we conducted a cross-sectional study in 2 independent cohorts of children aged 0 to 18 years with SCD (N = 1025 and N = 1293, respectively) and a 2957-person matched comparison group. Using a highly sensitive, error-corrected sequencing assay capable of detecting CH at a variant allele frequency of ≥0.5%, we found that children with SCD have a significantly higher prevalence of CH than the comparison group (odds ratio [OR], 4.2; P = 7.4 × 10−13). In addition, CH was not associated with exposure to hydroxyurea therapy (OR, 0.76; P = .44).