Browse Articles

Nicotinamide mononucleotide enhances semen quality during chilled storage of maguan hornless goat: mitigating oxidative damage at 4 °C

Robust and generalizable atrial fibrillation detection from ECG using time-frequency fusion and supervised contrastive learning

Finite element thermoelastic analysis of functionally graded spherical shells

Associations of sustainable and healthy nutrition, perceived stress, and brain fog with academic performance among university students

Context-sensitivity and longitudinal stability of the effects of depressive symptoms on social and reward decision-making

Effect of modeling liquid and glycerin application protocols on the surface roughness and microhardness of one shade resin composites

Effects of diets containing fish proteins or poultry proteins on one-carbon metabolites in domestic dogs. A randomised, double-blind, two-period cross-over study

Abstract Disturbances in the one-carbon metabolic pathways are linked with several diseases, and an elevated homocysteine concentration is correlated with increased risk for developing cardiovascular diseases. Fish intake reduces homocysteine concentration in some studies, whereas little is known whether other metabolites in the one-carbon pathways are affected. Most pre-clinical studies utilise rodents, but domestic dogs may be a superior alternative model for research on human nutrition. The aim of this study was to compare the effects of diets containing proteins from herring or poultry on serum concentrations of homocysteine and related one-carbon metabolites in domestic dogs. Forty home-living golden Retrievers and Labrador Retrievers were included and received each of the two experimental diets for eight weeks in this cross-over trial. Thirty-five dogs were included in the biochemical and statistical analyses. Within-group changes were compared using the Mann-Whitney U Test. The serum concentrations of homocysteine, sarcosine, cystathionine and serine were reduced after intake of either herring or poultry protein diets, with no differences between the groups. The serum betaine concentration was increased by both diets, with a more pronounced increase after poultry protein intake, whereas choline concentration was not affected by either diet. Methionine and cysteine concentrations were not affected by herring protein, but were decreased and increased, respectively, after poultry protein intake. The glycine concentration was reduced by both diets. Both herring and poultry proteins affected the one-carbon metabolism, with only marginal differences between the diets.

Sustainable computational fluid dynamics optimization of heat sink performance for energy efficient device cooling

High-Risk Smoldering Multiple Myeloma: A Review of Controversies in Early Treatment Versus Observation

Smoldering multiple myeloma (SMM) is an asymptomatic but biologically heterogeneous plasma cell disorder with a variable risk of progression to multiple myeloma (MM). Accurate risk stratification is essential as only a subset of patients—defined as high-risk SMM —faces a ≥50% risk of progression within 2 years. Contemporary approaches integrating clinical variables, dynamic biomarkers, genomic alterations, and immune profiling have improved risk assessment although some limitations remain. The therapeutic paradigm of SMM is evolving. Randomized phase III trials have consistently shown that early treatment delays progression to MM. Most recently, daratumumab monotherapy became the first approved treatment for high-risk-SMM following the AQUILA trial, which demonstrated a significant progression-free survival benefit (hazard ratio [HR], 0.49 [95% CI, 0.36 to 0.67], P < .001) and a trend toward improved overall survival (OS; HR, 0.52 [95% CI, 0.27 to 0.98]) versus observation. This approval challenges the traditional watch-and-wait approach and establishes early intervention as a validated option for selected patients. However, important uncertainties persist. With modern surveillance and advanced imaging, most progression events are asymptomatic and irreversible end-organ damage is uncommon. OS benefit from early treatment remains inconclusive, particularly in the era of quadruplet regimens available at MM progression. In addition, difficulties in precisely identifying truly high-risk patients raise concerns about overtreatment. Emerging data from intensive regimens, bispecific antibodies, and chimeric antigen receptor -T cell therapies suggest that deep and durable responses—and possibly cure—may be achievable in selected patients with high-risk-SMM, but long-term benefit and safety require further study. In conclusion, following the approval of daratumumab, SMM management should be risk-adapted and patient-centered: observation remains appropriate for some patients, while early treatment should be considered for carefully selected high- and ultrahigh-risk individuals.

Limiting Dexamethasone Exposure With Highly Emetogenic Chemotherapy Regimens: Is the Verdict In?

Microclone with megaimpact

Dexamethasone-Free Antiemetic Prophylaxis for Children and Adolescents Receiving Highly Emetogenic Chemotherapy: A Multicenter, Phase III, Noninferiority Trial (CIVIC POD)

PURPOSE Dexamethasone combined with a 5-hydroxytryptamine-3 receptor antagonist and a neurokinin-1 receptor antagonist is the guideline-recommended prophylaxis for chemotherapy-induced nausea and vomiting (CINV) in children receiving highly emetogenic chemotherapy (HEC), but it is associated with clinically relevant toxicities. The role of olanzapine as a dexamethasone-sparing agent for pediatric CINV prophylaxis remains uncertain. METHODS The Chemotherapy Induced Vomiting in Children-Prophylaxis Omitting Dexamethasone (CIVIC POD) was an investigator-initiated, multicenter, open-label, phase III, randomized noninferiority (NI) trial (INPHOG-SUPP-22-03) that enrolled patients age 4-18 years scheduled to receive single- or multiday HEC. Patients were randomly assigned 1:1 to dexamethasone, palonosetron, and fosaprepitant (DEX) or olanzapine, palonosetron, and fosaprepitant (OLANZ) for one chemotherapy cycle. The primary end point was complete response (CR) to vomiting (no vomiting and no rescue antiemetics) during the overall period (0-120 h after last chemotherapy). The prespecified NI margin was –15%. RESULTS A total of 310 patients were randomly assigned (DEX, n = 156; OLANZ, n = 154). The median age was 13 years, 62.3% were male, and 51.9% received multiday chemotherapy. The per-protocol population included 299 patients (DEX, n = 151; OLANZ, n = 148). The overall-period CR to vomiting was 56.9% with DEX and 63.5% with OLANZ (absolute difference, 6.6% [95% CI, −4.5 to 17.7]), meeting NI criteria. Acute-period CR to vomiting was 64.2% versus 68.9%, and delayed-period CR was 78.8% versus 79.1% (DEX v OLANZ). CR to nausea during the overall, acute, and delayed periods was 54.3% versus 53.4%, 59.6% versus 59.5%, and 69.5% versus 68.9%, respectively. Any-grade somnolence was more frequent with OLANZ (50.7% v 17.2%). CONCLUSION A dexamethasone-free regimen using olanzapine demonstrated noninferior control of vomiting compared with standard prophylaxis in children and adolescents receiving HEC, supporting olanzapine as a potential corticosteroid-sparing alternative for pediatric CINV prophylaxis.

Biallelic loss-of-function mutations in <i>BPNT1</i> cause vitamin B12–dependent megaloblastic anemia

Abstract We identified biallelic loss-of-function BPNT1 mutations in 3 patients with recurrent vitamin B12–dependent megaloblastic anemia. Mechanistically, BPNT1 deficiency caused the accumulation of PAP (3′-phosphoadenosine 5′-phosphate), impaired ribosome biogenesis, and reduced ileal expression of the cubilin/amnionless receptor complex in Bpnt1-null mice.

Erratum: Selinexor Plus Ruxolitinib in Janus Kinase Inhibitor–Naïve Myelofibrosis: Phase III SENTRY Trial

Single-cell MRD: from detection to direction

MLL3 and MLL4 sustain hematopoietic stem cell multipotency by opposing a B-cell default state

Abstract Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) are sustained by networks of transcription factors and epigenetic regulators that prime lineage-specific programs yet maintain multipotency. Two epigenetic regulators, MLL3 and MLL4, play important but distinct roles in maintaining this balance. MLL3 promotes HSC differentiation, whereas MLL4 opposes differentiation. These activities are essential for both normal homeostasis and leukemia suppression, yet it is not clear how MLL3 and MLL4 regulate HSC and MPP gene expression to control HSC/MPP fate decisions. To resolve these mechanisms, we performed an extensive series of single-cell genomic studies after conditionally deleting Mll3, Mll4 or both genes together. Mll3 deletion had only limited effects on HSC/MPP enhancer networks at steady state, whereas Mll4 deletion led to precocious activation of myeloid enhancers. Surprisingly, compound Mll3/4 deletion eliminated all myeloid, erythroid, and megakaryocytic potential within the hematopoietic hierarchy and caused all progenitors to rapidly default to a B-cell–like identity. These changes were accompanied by widespread inactivation of HSC/MPP enhancers and superenhancers and ectopic activation of B-cell superenhancers. Disabling MLL3/4 histone methyltransferase activity did not recapitulate the pervasive changes in cell identity that were observed when MLL3 and MLL4 were fully inactivated, indicating that MLL3 and MLL4 activate HSC/MPP enhancers independently from their enzymatic activities. Our findings show that HSC/MPP multipotency requires sustained tension between MLL3/4-dependent enhancers that maintain myeloid, erythroid, and megakaryocyte potential and MLL3/4-independent enhancers that prime B-cell identity. MLL3 and MLL4 therefore serve as critical linchpins of multilineage hematopoiesis.

Crumpled cytoplasm, clear diagnosis: the iconic morphology of Gaucher disease

Inhibition of high CXCR4 with motixafortide and absence of single-cell MRD predict outcome after AML consolidation

Abstract Relapse after remission remains the primary cause of treatment failure in acute myeloid leukemia (AML), underscoring the need for strategies to eliminate residual leukemic cells. The bone marrow (BM) microenvironment, largely orchestrated by the CXC chemokine receptor 4 (CXCR4)–CXC motif chemokine 12 axis (CXCL12), enables leukemia cell survival and chemoresistance by anchoring blasts in their protective BM niche. Motixafortide, a selective CXCR4 antagonist, mobilizes leukemic cells and disrupts tumor microenvironment interactions in preclinical models. In this randomized, double-blind, placebo-controlled phase 2 trial, 128 patients in first remission received high-dose cytarabine plus motixafortide or placebo. Median relapse-free survival did not substantially differ between groups: 10.3 months (95% confidence interval [CI], 8.0-12.0) for motixafortide and 11.5 months (95% CI, 8.6-24.1) for placebo (log-rank P = .98). But single-cell measurable residual disease (scMRD) analysis, performed before consolidation, demonstrated heterogeneity of CXCR4 inhibition benefit; in the placebo group, higher CXCR4 expression was associated with increased relapse risk (P = .02), whereas in the motixafortide group, higher CXCR4 expression was linked to a reduced relapse rate (P = .047). Exploratory analyses identified scMRD levels at which higher MRD burden was associated with inferior overall survival. Taken together, combining functional MRD profiling with biomarker-driven patient selection, such as CXCR4 expression, may enable more precise and effective postremission interventions in AML. This trial was registered at www.clinicaltrials.gov as NCT02502968 and at EudraCT as 2014-002702-21.

Prognostic impact of <i>FLT3</i> -ITD microclones in young adults with acute myeloid leukemia treated with intensive chemotherapy

Abstract FLT3 internal tandem duplications (FLT3-ITD) are major genetic events in acute myeloid leukemia (AML). Although the clinical impact of FLT3-ITD “macroclones” (allelic ratio [AR] ≥0.05) is well established, the significance of low-level FLT3-ITD subclones (“microclones”) remains uncertain. We conducted a post hoc analysis of 1733 patients with newly diagnosed AML enrolled in the Backbone Intergroup 1 trial (ClinicalTrials.gov identifier: NCT02416388). Using next-generation sequencing (NGS), we detected FLT3-ITD microclones (AR between 0.0004 and 0.05) in 17.4% of patients without FLT3-ITD macroclones. Microclones and macroclones (low and high AR) were independently associated with increased relapse risk (cause-specific hazard ratio, 1.50 [95% confidence interval (CI), 1.18-1.91]; 1.98 [1.50-2.62]; and 2.33 [1.69-3.22], respectively) after adjustment for age, white blood cell count, other gene mutations, midostaurin treatment, and allogeneic hematopoietic stem cell transplantation. At 2 years, the cumulative incidence of relapse reached 42.5% (95% CI, 37.0-47.9) in patients with macroclones, 45.1% (38.3-51.6) in patients with microclones, and 29.4% (26.6-32.3) in patients without FLT3-ITD. In NPM1-mutated AML, both microclones and macroclones were associated with higher levels of measurable residual disease (MRD) and increased relapse risk, without independent impact on overall survival after adjustment for MRD. An analysis of paired samples further revealed that 41.8% of relapses in patients with FLT3-ITD microclones at diagnosis were associated with a macroclone at relapse. These findings challenge current risk stratification models and support the integration of NGS-based FLT3-ITD detection into the diagnostic and prognostic workflow for AML. Prospective trials addressing the management of patients with FLT3-ITD microclones are warranted, as is their consideration in future European LeukemiaNet guidelines.

Chronic pain in sickle cell disease: a role for lysophosphatidic acid

Abstract Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by persistent pain. The mechanisms underlying pain in SCD are poorly understood, and opioids remain the primary treatment, despite their severe side effects. Here, we investigated the contribution of lysophosphatidic acid (LPA), an endogenous pronociceptive lipid mediator, to chronic pain in SCD using humanized transgenic homozygous Berkeley mice that express &amp;gt;99% human sickle hemoglobin (HbSS) and control HbAA mice that express normal human hemoglobin A. Hyperalgesia in HbSS mice was associated with an increase in both plasma level of LPA and expression of LPA receptor 1 (LPA1R) mRNA in L1 to L5 dorsal root ganglion (DRG). Blocking LPA synthesis with BI-2545, or blocking LPA1R function with small interfering RNA (siRNA) or the LPA1R antagonist, AM966, reversed mechanical and heat hyperalgesia in HbSS mice. LPA also produced acute mechanical and heat hyperalgesia in HbAA mice, which resulted from the sensitization of C-fiber nociceptors. In HbSS mice, hyperalgesia was associated with sensitization of nociceptive DRG neurons. Nociceptors from hyperalgesic HbSS mice had lower rheobase, more positive resting membrane potential, and higher frequency of action potential. Although no changes were found in the values of inward currents in nociceptors of HbSS mice compared with HbAA mice, outward-inactivating and noninactivating currents were reduced, indicating the importance of potassium channels to sensitization in SCD. All these parameters were normalized by pretreatment of HbSS mice with LPA1R siRNA. Our results suggest that LPA signaling may be a promising target for treating pain in SCD.