Citations

ABSTRACT Patients with newly‐diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax (Ven) plus hypomethylating agent (HMA) therapy, and the optimal Ven duration across genetic risk groups remains undefined. Among 540 ND‐AML patients receiving Ven‐HMA at Mayo Clinic, outcomes were compared across Ven 7‐ ( n = 33), 14‐ ( n = 117), 21‐ ( n = 96), and 28‐day ( n = 294) schedules during Cycle 1 and stratified by ELN 2024 and Mayo genetic risk groups. At a median follow‐up of 37.7 months, allogeneic stem cell transplant (ASCT) rates were similar across Ven duration groups (15%, 18%, 18%, and 20% for 7‐, 14‐, 21‐, and 28‐day; p = 0.86). Median transplant‐censored survival was comparable across Ven durations (13.3, 11.9, 16.8, and 13.2 months for 7, 14, 21, 28 days, respectively; p = 0.65), with outcomes driven by ELN risk (6.3, 11.5, 18.3 months for high, intermediate, low; p < 0.01) and Mayo genetic risk (6.9, 17.8 months, not reached; p < 0.01). Survival was comparable across Ven durations within ELN intermediate/low‐risk and all Mayo risk groups. Among ELN high‐risk patients, 14‐day Ven was associated with inferior transplant‐censored survival compared to 21‐ and 28‐day schedules ( p < 0.01). Notably, 30‐ and 60‐day mortality were higher with shorter Ven schedules (7‐day: 9%/18%; 14‐day: 7%/15%) versus 28‐day (2%/6%), which likely reflects treatment selection bias. In ND‐AML, no significant difference in transplant‐censored survival was observed across the 7‐, 14‐, 21‐, and 28‐day Ven schedules; prognosis was determined primarily by Mayo and ELN 2024 genetic risk rather than by Ven duration. Prospective trials are needed to establish risk‐adapted Ven dosing strategies.

Messenger RNA (mRNA) therapeutics have transformed vaccination and protein replacement strategies, yet efforts to improve their performance have focused largely on sequence engineering, nucleotide modification, and delivery vehicles. Here we show that mRNA function can be controlled by rational design of higher-order RNA architectures. We develop self-assembling mRNA origami (mRNA-OG), a class of unimolecular RNA nanostructures that encode protein-coding sequences within higher-order, programmable, and compact nucleic acid architectures. Using computational design and experimental validation, we demonstrate that mRNA-OG folds into well-defined nanostructures while remaining translationally competent in mammalian cells. Although folded mRNA-OG recruits ribosomes comparably to unfolded constructs, it produces lower protein output, indicating that RNA architecture can directly influence translational efficiency. The compact geometry of mRNA-OG also enhances encapsulation by cationic lipid delivery systems, suggesting a structural route to improved cargo packaging. Beyond its effects on translation, mRNA architecture modulates innate immune recognition. In primary human dendritic cells, folded and unfolded mRNA-OG elicit distinct cytokine programs and differential activation of stress-response pathways, including a modest induction of the integrated stress response that is not fully explained by canonical PKR signaling. Our results establish programmable structure as a new design parameter for mRNA therapeutics that can affect its functionality, delivery properties, and immune sensing.

Odontogenic myxoma (OM) is an uncommon, locally aggressive odontogenic neoplasm with characteristic histologic and clinico-radiographic features but with potential for histologic overlap with other odontogenic and non-odontogenic entities and a non-specific immunoprofile. Widespread loss of heterozygosity (LOH) has been recently described in rare cases of OM. The aim of this study was to determine whether widespread LOH represents a recurrent molecular signature that can be leveraged for clinical decision-making. Allele-specific copy number variation data from chromosomal microarray were generated from 7 OM, comprising a combined prospective and retrospective cohort. Four tumors arose in the mandible and 3 in the maxilla in patients ranging in age from 18 to 94 years (median: 44), with tumor size ranging from 2.2 to 13.0 cm. Variable amounts of fibrous stroma (odontogenic “fibromyxoma”) were present in 4/7 OM, and hypercellularity not typically appreciated in conventional OM was present in 3/7 cases. All OM (7/7) demonstrated widespread LOH, with 5 cases showing a near-haploid/low hypodiploid genomes (multiple monosomies) and 2 cases showing evidence of pseudo-hyperdiploidy due to probable endoreduplication. Both pseudo-hyperdiploid cases were ≥10 cm in size; 1 represented local recurrence. Chromosomes 1 to 3, 6, 9, 11, 13, 15, and 22 demonstrated LOH in ≥75% of cases (chromosomes 1 to 3, 6, and 9 in 100% of cases), while chromosomes 5, 12, 19, and 20 universally retained heterozygosity. Altogether, widespread LOH is a recurrent event in OM and a novel finding in odontogenic pathology, and allele-specific copy number variation analysis can serve as a diagnostic adjunct in challenging cases.

Summary Background Clonal haematopoiesis (CH), the age-related expansion of mutated blood stem cells, is detectable in around 10% of people in their seventies, rises steeply with age, and is associated with several diseases. Its relationship with neurodegeneration remains contentious, with conflicting evidence for both protective and detrimental effects on Alzheimer’s disease (AD). Methods Here, we applied COMET, a mutation-agnostic, methylation-based predictor of clonal haematopoiesis burden that estimates predicted VAF (pVAF), to examine longitudinal associations between clonal burden and brain structure in the Lothian Birth Cohort 1936. In addition, to capture broader clonal burden, we developed CIMS, a novel methylation-based score derived from clonal haematopoiesis of indeterminate potential (CHIP) EWAS summary statistics, which reflects the epigenetic profile of both mutant and wild-type blood immune cells. Blood DNA methylation and structural MRI data were available at three timepoints spanning ages 73–79 years. The analytic dataset comprised 1,091 participants, of whom 808 (pVAF) and 836 (CIMS) contributed clonality data and 744 had brain MRI; 479–481 had complete baseline and longitudinal imaging measures with covariates. Trajectories were modelled with latent growth curve models fitted by full information maximum likelihood. Findings Longitudinal trajectories of clonality and grey matter volume were significantly associated over 6 years (Std. est. = −0.176, p adj = 0.030), revealing a progressive, left-lateralised cortical atrophy pattern affecting medial temporal and parietal regions. This pattern showed significant spatial correspondence with established AD signatures ( r = 0.357, p = 0.003), suggesting that clonality is linked to AD-related patterns of neurodegeneration. Subcortical analyses revealed nominal relative preservation of the caudate and did not detect a statistically significant association with hippocampal volume, suggesting potential divergence from the canonical AD subcortical profile. The CIMS confirmed global atrophy but revealed divergent tissue-type and regional patterns, suggesting the two measures may capture distinct aspects of CH biology. Interpretation Together, these findings suggest that CH burden may mark biological processes associated with structural brain atrophy in cognitively healthy older adults, with clonality showing a regional pattern that resembles the one reported in AD. CH burden may therefore be a candidate marker of adverse brain ageing; whether it tracks AD pathology in particular, rather than age-related neurodegeneration more broadly, remains to be tested.

Aims Two-stage exchange arthroplasty with an antibiotic-eluting cement spacer remains the predominant strategy in the USA for managing chronic periprosthetic joint infection (PJI) following total hip arthroplasty (THA). The aim of this study was to evaluate a commercially available, partially intraoperatively fabricated articulating high-dose antibiotic cement spacer, focusing on survival, complications, and patient-reported outcomes. Methods A total of 298 patients (302 THAs) underwent two-stage exchange arthroplasty for PJI using a specific articulating antibiotic spacer between August 2005 and May 2022. Patients with a previous failed two-stage exchange were excluded, although 121 THAs (302, 40%) had undergone previous PJI-related procedures. The mean age of the patients was 65 years (SD 11), the mean BMI was 32 kg/m 2 (SD 7), and 116 (38%) were female. Most patients were classified as McPherson host B (158; 52%) and limb grade 2 (165; 55%), and 265 (88%) met the 2011 Musculoskeletal Infection Society criteria. The mean follow-up was six years (2 to 16). Results At five years after reimplantation, survival free of reinfection, aseptic rerevision, any rerevision, or any reoperation were 89% (95% CI 85.2 to 93.1), 93% (95% CI 89.3 to 96.1), 86% (95% CI 81.3 to 90.3), and 80% (95% CI 74.7 to 84.9), respectively. Dislocation accounted for most aseptic rerevisions (15/20). McPherson host C (HR 3.7 (95% CI 1.4 to 9.6); p = 0.007) and limb grade 3 (HR 3.3 (95% CI 1.0 to 11.1); p = 0.049) were significantly associated with an increased risk of reinfection. The mean Harris Hip Score at the latest follow-up was 76 (29 to 100). A total of 17 patients underwent revision or removal of a spacer for concerns about persistent infection and two for dislocation of the spacer. Eight patients underwent a non-rerevision reoperation during the spacer interval for wound drainage (n = 5), dislocation of the spacer (n = 2), and perispacer fracture (n = 1). A total of 26 spacer-related complications were treated nonoperatively (15 perispacer fractures, 11 dislocations). Dislocation of the spacer was strongly associated with dislocation after reimplantation (HR 6.2 (95% CI 2.3 to 16.9); p < 0.001). Conclusion This commercially available, partially intraoperatively fabricated articulating spacer showed excellent reinfection-free five-year survival (89%). Spacer-related fracture and dislocation each occurred in 5% of patients. Dislocation of the spacer significantly increased the risk of dislocation following reimplantation, supporting the use of higher-stability bearings in these high-risk patients. Cite this article: Bone Joint J 2026;108-B(9):1104–1112.