Citations

AbstractBackgroundNeuropathologic inclusions formed by hyperphosphorylated protein tau in the brain are a hallmark of Alzheimer’s disease and other human neurodegenerative disorders commonly referred to as tauopathies. Tau lesions differ in their disease‐specific morphological presentations, affected cell type, subcellular compartments and tau isoforms present in the inclusions. In addition, tau filaments isolated from different tauopathies have distinct fibrillar structures that potentially underlie the morphological diversity of tau lesions. The factors that govern the formation of disease‐specific tau lesions and distinct patterns of neurodegeneration and clinical presentations are unknown. To address this gap of knowledge, we performed profiling of proteomes associated with phospho‐tau aggregates in 4 major tauopathies.MethodWe utilized the in‐house developed Probe‐dependent Proximity Profiling (ProPPr) method combined with data‐independent acquisition mass spectrometry to profile phospho‐tau associate proteomes in formalin‐fixed paraffin‐embedded (FFPE) frontal cortex tissue sections from the Mayo Clinic Florida Brain Bank. Selected candidates were validated by fluorescent co‐immunostaining of patient brains with corresponding antibodies.ResultIn situ proximity proteomic profiling revealed over 1300 protein associated with phospho‐tau pathology, including 229 proteins that were identified in all tauopathies. The most significantly enriched GO terms in this protein set common to all the tauopathies were related to chaperone activity, guanyl nucleotide binding, cadherin binding, cytoskeleton, and ion transporter activity, highlighting biological processes and pathways affected by tau aggregation regardless of the type of tau lesion. In addition, we identified 32 proteins with significantly different association with phospho‐tau between tauopathies. Immunostaining of post‐mortem patient frontal cortices confirmed some of the findings from proteomics and revealed differences in abundance and localization patterns of several tau‐associated proteins between tauopathies, uncovering a potential of using these proteins as biomarkers for antemortem diagnosis.ConclusionTau lesions in different tauopathies have differences in their associated proteomes that can be assessed by the ProPPr assay.

PURPOSE In light of evolving evidence that some patients with node-positive estrogen receptor–positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes of the C9741 trial overall, and by the sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring endocrine transcriptional activity, to identify patients most likely to benefit from dose-dense chemotherapy. METHODS In all, 1,973 patients were randomly assigned to dose-dense versus conventional chemotherapy. Hazard ratios (HRs) for prognosis and for predictive interaction with chemotherapy schedule were estimated from Cox models of long-term disease-free survival (DFS) and overall survival (OS). SET2,3 was tested on the 682 banked RNA samples from ER+ cancers. RESULTS Dose-dense chemotherapy improved DFS in the overall study population by 23% (HR, 0.77 [95% CI, 0.66 to 0.90]) and OS by 20% (HR, 0.80 [95% CI, 0.67 to 0.95]); the benefits of dose-dense therapy were seen for ER+ and ER-negative subsets, without significant interaction between treatment arm and ER status. Low SET2,3 status was highly prognostic, but also predicted improved outcomes from dose-dense chemotherapy (interaction P = .0998 for DFS; 0.027 for OS), independent of menopausal status. Specifically, low endocrine transcriptional activity predicted benefit from dose-dense chemotherapy, whereas tumor burden and proliferation-driven signatures for molecular subtype classification did not. CONCLUSION At 12-year follow-up, C9741 confirmed the sustained long-term benefit of adjuvant dose-dense chemotherapy for node-positive breast cancer. SET2,3 identified patients with ER+ breast cancer who benefited from dose-dense chemotherapy, and specifically, this benefit was predicted by low endocrine activity in the cancer, rather than tumor burden, molecular subtype, or menopausal status.

AbstractBackgroundThe clinical significance of natural and treatment‐emergent antibodies specific for amustaline/glutathione pathogen‐reduced red blood cells (PRRBCs) is not known.Study Design and MethodsA Phase 3, randomized clinical trial of PRRBCs (ReCePI) compared PRRBCs with conventional RBCs in cardiac or thoracic‐aorta surgery. Subjects transfused during and for 7 days after surgery were screened for PRRBC‐specific antibodies at baseline, 28 and 75 days post‐surgery. Subjects with treatment‐emergent antibodies were assessed for evidence of hemolysis. Cryopreserved subject RBC samples were assayed by flow cytometry for circulating PRRBCs using an acridine‐specific (2S197‐2M1) monoclonal antibody, and for human IgG‐coated RBCs. RBC‐surface acridine density was quantitated using a commercial calibrated phycoerythrin (PE)‐bead panel.ResultsFive of 159 (3.1%) PRRBC and zero of 162 conventional RBC recipients developed treatment‐emergent PRRBC‐specific IgG, low titer antibodies detected 26–80 days post‐surgery after exposure to 1–3 PRRBC units, without clinical evidence of hemolysis. DAT and eluate were weak (w+) positive and PRRBC‐specific in one subject. A monocyte monolayer assay (MMA) was non‐reactive in the three subjects with an interpretable result. Flow cytometry demonstrated circulating PRRBCs in all five subjects expressing surface acridine concentrations at the limit of detection (approximately 150–301 PE molecules/RBC) compared with freshly transfused PRRBCs (approximately 7500 PE molecules/RBC). In some samples, loss of surface acridine expression could not be distinguished from clearance of the PRRBCs.DiscussionTreatment‐emergent PRRBC‐specific antibodies with the characteristics of nonclinically significant antibodies were detected in five subjects transfused with PRRBCs. Flow cytometry demonstrated persistent circulating PRRBCs with minimal surface acridine expression. (www.ClinicalTrials.gov Identifier NCT03459287).

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has surged as a major cause of liver transplants in the United States. Existing studies have presented conflicting findings regarding the association between liver characteristics (specifically steatosis and fibrosis) and mortality. This study investigates the relationship between the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) and all-cause mortality in MASLD patients. Methods: Using the NHANES 2017-2018 database, 3821 individuals representing the United States population with MASLD underwent VCTE for liver stiffness measurement. Exclusion criteria were applied, eliminating ineligible cases, incomplete examinations, underage individuals, and those with hepatitis B or C, along with significant alcohol consumption history. Cox proportional hazard models assessed the hazard ratio (HR) for all-cause mortality in CAP and LSM. Cox regression analysis with interaction terms was employed for deeper exploration. Results: The study unveiled a strong, independent correlation between LSM and all-cause mortality. However, the CAP failed to demonstrate a significant association with mortality in both univariate and adjusted analyses, contrary to recent findings. The analysis underscores the importance of accurately measuring liver stiffness via VCTE in predicting adverse outcomes in MASLD patients, emphasizing the pivotal role of fibrosis in assessing mortality risk. Conclusion: This study reaffirms the robust link between liver fibrosis (measured through VCTE) and mortality among MASLD individuals. The absence of a significant association between steatosis (indicated by CAP) and mortality challenges recent research, urging further comprehensive investigations with larger cohorts to delineate steatosis’ precise impact on MASLD-related mortality.

Abstract As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, whereas 2 keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.

Abstract The interactions between transcription factors (TFs) and the target genes could provide a basis for constructing gene regulatory networks (GRNs) for mechanistic understanding of various biological complex processes. From gene expression data, particularly single-cell transcriptomic data containing rich cell-to-cell variations, it is highly desirable to infer TF–gene interactions (TGIs) using deep learning technologies. Numerous models or software including deep learning–based algorithms have been designed to identify transcriptional regulatory relationships between TFs and the downstream genes. However, these methods do not significantly improve predictions of TGIs due to some limitations regarding constructing underlying interactive structures linking regulatory components. In this study, we introduce a deep learning framework, DeepTGI, that encodes gene expression profiles from single-cell and/or bulk transcriptomic data and predicts TGIs with high accuracy. Our approach could fuse the features extracted from Auto-encoder with self-attention mechanism and other networks and could transform multihead attention modules to define representative features. By comparing it with other models or methods, DeepTGI exhibits its superiority to identify more potential TGIs and to reconstruct the GRNs and, therefore, could provide broader perspectives for discovery of more biological meaningful TGIs and for understanding transcriptional gene regulatory mechanisms.

ObjectiveVagus nerve stimulation (VNS) paired with rehabilitation therapy improved motor status compared to rehabilitation alone in the phase III VNS‐REHAB stroke trial, but treatment response was variable and not associated with any clinical measures acquired at baseline, such as age or side of paresis. We hypothesized that neuroimaging measures would be associated with treatment‐related gains, examining performance of regional injury measures versus global brain health measures in parallel with clinical measures.MethodsBaseline magnetic resonance imaging (MRI) scans in the VNS‐REHAB trial were used to derive regional injury measures (extent of injury to corticospinal tract, the primary regional measure; plus extent of injury to precentral gyrus and postcentral gyrus; lesion volume; and lesion topography) and global brain health measures (degree of white matter hyperintensities, the primary global brain measure; plus volumes of cerebrospinal fluid, cortical gray matter, white matter, each thalamus, and total brain). Eight clinical measures assessed at baseline were also evaluated (treatment group, age, race, gender, paretic side, pre‐stroke dominant hand, time since stroke, and baseline Fugl‐Meyer upper extremity score). Bivariate analyses compared each measure with the primary trial end point (change in Fugl‐Meyer upper extremity score from baseline to end of 6 weeks of treatment) across all subjects, with secondary analyses examining trial groups separately.ResultsMRIs were available from 80 patients (age = 59.8 ± 9.5 years, 29 women). Across all patients, less white matter hyperintensities (r = −0.25, p = 0.028) at baseline was associated with larger Fugl‐Meyer score change. In the VNS group, less white matter hyperintensities (r = −0.37, p = 0.018) and larger ipsilesional thalamus volume (r = 0.33, p = 0.046) were each associated with larger Fugl‐Meyer score change. Analysis of covariance (ANCOVA) analyses tested the interaction that each baseline measure had with treatment group and found that the model examining white matter hyperintensities had a significant interaction term, indicating 2.3 less change in Fugl‐Meyer Upper Extremity (FM‐UE) points in the VNS group relative to the control group for each point increase in modified Fazekas scale.InterpretationNeuroimaging measures are associated with extent of gains on the primary endpoint of a phase III stroke recovery trial. Among the neuroimaging measures examined, a measure of global brain health (extent of white matter hyperintensities) was better at explaining the change in arm impairment as compared with measures of regional injury; this was true when examining all study subjects as well as only those in the VNS group and is consistent with the global mechanism of action that VNS has throughout the cerebrum. Future studies can evaluate additional measures that further predict response to VNS therapy. The current findings suggest that individual patient neuroimaging results may be useful for a personalized medicine approach to stroke recovery therapeutics. ANN NEUROL 2025;97:709–719

Background Migraine is associated with obesity. These analyses evaluated weight change with atogepant used as a preventive migraine treatment. Methods Five atogepant clinical trials in adults with migraine (one phase 2b/3; four phase 3) were included: Three 12-week, randomized, placebo-controlled trials (episodic migraine: two; chronic migraine: one); one 40-week, open-label extension trial and one 52-week, standard care, randomized, long-term safety trial in episodic migraine. Change from baseline in body weight was measured. Results Mean baseline body mass indexes were 30.0–30.7 kg/m 2 (pooled episodic migraine [United States only]) and 25.0–25.5 kg/m 2 (chronic migraine [East Asia, Europe, and North America]). More participants treated with atogepant 60 mg once-daily compared to placebo experienced ≥7% weight loss at any time in the pooled episodic migraine placebo-controlled trials (4.9% vs. 2.8%), chronic migraine placebo-controlled trial (5.8% vs. 2.0%), and pooled open-label extension and long-term safety trials (24.0% vs.14.7% in standard care [long-term safety only]). In the placebo-controlled trials, weight loss with atogepant 60 mg once-daily was observed at week 2 (pooled episodic migraine: −0.32%; chronic migraine: −0.39%), increasing at week 12 (pooled episodic migraine: −1.02%; chronic migraine: −1.50%); compared to weight gain with placebo at week 12 (pooled episodic migraine: +0.49%; chronic migraine: +0.10%). In the long-term episodic migraine studies, weight loss with atogepant 60 mg once-daily was observed at week 4 (long-term safety: −0.42%; open-label extension: −0.76%), increasing at week 40 (long-term safety: −2.38%; open-label extension: −2.09%). Conclusion Atogepant was associated with modest dose- and duration-dependent weight loss. Trial registration ClinicalTrials.gov identifiers: NCT02848326 (CGP-MD-01); NCT03777059 (3101-301-002); NCT03700320 (long-term safety trial); NCT03939312 (open-label extension trial); NCT03855137 (3101-303-002).

NPM1 mutations (NPM1+) are found in about 30% of adult AML. While NPM1+ are generally associated with favorable risk, prior studies have shown that NPM1+ older patients, defined as ≥ 65 years, have significantly worse outcomes. The updated European Leukemia Net 2022 (ELN22) now classifies NPM1+ AML patients with FLT3-ITD (ITD+) and MDS-associated mutations (MDSm+) as adverse-risk, while NPM1+/ITD-/MDSm+ patients remain favorable-risk unless they have an adverse-risk karyotype. A recent report (Chan et al., Blood Adv 2024) found MDSm+ conferred worse OS only in patients ≥ 60 years; however another report (Othman et al., Blood 2024) did not find MDSm+ were significantly associated with adverse outcomes in a larger cohort of NPM1+ patients. To further assess this question, we examined the mutational landscape in a large cohort of pre-treatment, diagnostic specimens from 456 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112) and 126 patients from the UW/FHCC Hematopoietic Repository (Total N=582). Patients were treated with curative intent as per standard practice or clinical trials. Out of the 582 patients, 191 were NPM1+ (33%), of which 148 patients had cytogenetic and long-term outcome data. Kaplan-Meier and cumulative incidence estimates were estimated. C-statistics and AUC for Cox, cause-specific and logistic regression models for overall survival (OS), event-free survival (EFS), time to relapse (TTR, calculated in n=106 who achieved complete remission [CR], death in remission analyzed as a competing risk) and CR were calculated for age, ELN17, and ELN22, as well as ELN17 and ELN22 adjusting for age. ELN17 favorable-risk patients reclassified as adverse-risk (N=5 of 108) demonstrated significantly shorter EFS (HR=2.50, p=0.05) and CR rate (OR=0.20, p=0.024), although with similar OS (HR 1.30, p=0.66) and TTR (HR=1.20, p=0.86). ELN17 favorable-risk patients reclassified as ELN22 intermediate-risk (N=23 of 108) did not show a significant difference in OS (HR 1.47, p=0.20), EFS (HR 1.35, p=0.12), CR rate (OR 0.75, p=0.46), or TTR (HR=1.64, p=0.11) compared to ELN22 favorable-risk. For ELN17 intermediate-risk (N=40), 5 patients were reclassified as ELN22 adverse-risk (12.5%) and had significantly shorter EFS (HR 2.89, p=0.037) compared to ELN22 intermediate risk, although there was not a significant difference in CR rate (OR 0.31, p=0.23) or OS (HR 0.81, p=0.67). We next compared the prognostic significance of age relative to ELN risk classification. Age was associated with higher C-statistics (OS=0.65, TTR=0.57 and EFS=0.60) and AUC (CR=0.64) compared to both ELN17 (OS=0.56, TTR=0.54, EFS=0.54, CR=0.54) or ELN22 (OS=0.57, TTR=0.57, EFS=0.57, CR=0.58). The combination of age and ELN22 resulted in the highest C-statistics for OS, TTR, and EFS (OS=0.68, TTR=0.60, EFS=0.64). To further assess the impact of MDSm on risk-stratification of NPM1+ AML, we performed multivariable analyses adjusting for FLT3-ITD, MDSm, and age in patients without adverse-risk disease. These analyses showed MDSm did not have a significant association with OS when controlling for age or FLT3-ITD. We also compared ELN22 favorable-risk patients with and without MDSm (MDSm+ N=18; MDSm- N=61). Compared with the MDSm-, there was a trend toward an inferior OS (HR 1.85, p=0.054) for MDSm+ patients but not EFS (HR 1.38, p=0.3) or TTR (HR 1.2, p=0.64). When stratified by age (<65, N=53 vs. ≥65, N=26), MDSm+ in younger patients did not show a difference for OS (HR 0.96, p=0.96), EFS (HR 0.63, p=0.53) or TTR (HR 0.4, p=0.37). Older ELN22 favorable-risk patients (≥65) had similarly poor OS (MDSm- HR 3.33 and MDSm+ 3.27, respectively, p=0.001 for both) and EFS (MDSm- HR 3.11 and MDSm+ 2.39, p=0.001 and 0.01) compared to younger MDSm- patients. In our study, the ELN22 guidelines incrementally improve risk stratification for EFS in NPM1+ patients. However, age remains the most prognostic factor, and patients ≥ 65 years have similar adverse clinical outcomes, whether classified as favorable risk by ELN17, ELN22, or incorporating MDSm. Moreover, MDSm do not confer a worse prognosis in NPM1+ patients when accounting for age or FLT3-ITD status. These findings differ from a recent report by Chan et al. and are in keeping with the report by Othman et al. Therefore, further understanding of the underlying biology of age and its effect on NPM1+ AML is needed to improve outcomes for older patients.