Citations

Abstract Background Molecular underpinnings and clinical characteristics of ERBB2/HER2-mutated colorectal cancers (CRCs) remain poorly understood. We aimed to comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated CRC and to compare them with those of ERBB2/HER2-amplified CRC. Patients and methods We analyzed cBioPortal data from 4348 CRC patients with available ERBB2/HER2 profiling. Clinicodemographic features, microsatellite instability (MSI), tumor mutational burden, and alterations in 94 cancer-associated genes were evaluated using chi-square/Fisher’s exact test, Kruskal–Wallis test, and hierarchical clustering. Results ERBB2/HER2 putative driver mutations were identified in 95 patients (2.2%), amplifications in 87 (2.0%), and wild-type status in 4166 (95.8%). In the overall cohort, ERBB2/HER2-mutated tumors demonstrated significant KRAS enrichment (50.5%) compared to wild-type (37.7%; P = .014) and amplified tumors (18.4%; P < .001), alongside MSI enrichment (37.2% vs 1.6%; P < .001), elevated tumor mutational burden, and right-sided predominance. ERBB2/HER2-mutated tumors also showed broad driver co-alterations largely reflecting their MSI background. In contrast, ERBB2/HER2-amplified tumors exhibited left-sided predominance, with microsatellite stable (MSS)-restricted analyses revealing selective mutual exclusivity with KRAS (Log2 OR = −1.58; q = 0.019) and TP53 co-occurrence (Log2 OR = 2.04; q = 0.019). Hierarchical clustering confirmed that mutated and amplified tumors consistently occupy separate clusters across anatomical sites. Conclusion ERBB2/HER2 mutations and amplifications represent molecularly and clinically distinct subgroups. ERBB2/HER2-mutated tumors are characterized by an MSI-enriched, hypermutated background with frequent concurrent KRAS alterations, whereas amplified tumors exhibit selective KRAS mutual exclusivity and TP53 co-occurrence. These exploratory findings support alteration-specific therapeutic strategies in CRC.

Background:The development of symptoms or left ventricular dysfunction in severe aortic stenosis (AS) is associated with high morbidity and mortality. While elective transcatheter aortic valve replacement (TAVR) is supported by robust randomized evidence, data on TAVR performed in non-elective settings (urgent, emergent, or salvage) remain limited and heterogeneous. In these settings, outcomes may be influenced more by baseline clinical severity than by procedural factors. This study aimed to systematically evaluate the safety and effectiveness of non-elective TAVR and to compare the associated outcomes with those of elective TAVR.Methods:This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO. The PubMed, Embase, and Scopus databases were searched for studies published after 2002 evaluating urgent, emergent, or salvage TAVR in adult patients with severe AS. Eligible studies were required to include elective TAVR as a comparator. Outcomes included mortality and major procedural complications. Prespecified era-based analyses and sensitivity analyses excluding studies at critical risk of bias were performed. Risk of bias was assessed using the ROBINS-I tool.Results:A total of 17 observational studies published between 2015 and 2025 were included, comprising 215,141 patients. Compared with elective patients, those undergoing non-elective TAVR had more advanced heart failure, higher NYHA class, greater comorbidity burden, and higher surgical risk scores, whereas baseline echocardiographic severity of AS was similar. Pooled outcomes for non-elective TAVR showed in-hospital, 30-day, and 1-year mortality rates of 5.1%, 12.4%, and 26.7%, respectively. Non-elective TAVR was associated with higher mortality at all time points compared with elective procedures; meanwhile, rates of stroke, vascular complications, and permanent pacemaker implantation were similar, while major bleeding and acute kidney injury were more frequent. Era-based analyses showed a stable relative mortality risk over time.Conclusions:Although non-elective TAVR is associated with worse outcomes than elective procedures, these differences appear to be largely driven by baseline clinical severity rather than by the transcatheter intervention. In unstable patients with severe AS, non-elective TAVR remains the most effective definitive treatment option compared with balloon aortic valvuloplasty or conservative management.The PROSPERO Registration:CRD420251239620, https://www.crd.york.ac.uk/PROSPERO/view/CRD420251239620.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

ABSTRACT Pediatric radiation therapy presents unique challenges compared to adult treatments, including those of immobilization, potential need for sedation, and the critical importance of accurate, reproducible positioning. Additionally, heightened attention to imaging doses is necessary to minimize long‐term toxicity in survivors. Many of these challenges must be addressed during the process of simulation. This report provides guidelines for pediatric radiotherapy simulation from the Children's Oncology Group. These guidelines cover all anatomic sites and include recommendations for photon and proton therapies, as well as specialized procedures such as stereotactic body radiation therapy, brachytherapy, and total body irradiation. These guidelines are presented as recommendations rather than prescriptive standards as the practice will vary depending on patient age, diagnosis, clinical judgment, and institutional resources.

Abstract Introduction The immune environment of the brain plays a major role in neurodegenerative conditions such as Alzheimer’s disease. The abnormally clean facilities in which laboratory mice are kept limit immune experience and cause major concerns regarding the translatability of research to humans. These facilities, although not germ-free, lack the normal exposures to diverse commensal and environmental microorganisms experienced by mice in the wild or diverse environments such as a pet store. By breeding inbred lab mice that have previously experienced exposure to the dirty bedding of pet store mice, we can generate “bred dirty” mice with immune systems that mirror those of adult humans more closely. It is unclear whether these immune changes extend to the brain and whether this plays a role in neurodegenerative disease. Methods We used the P301s transgenic mouse model of Alzheimer’s disease that accumulates age-dependent tau pathology. We exposed these mice to dirty bedding obtained from pet store mice, and bred them to establish a line of “bred dirty” tau-P301S mice and appropriate controls. At endpoint, we collected brain and spleen for flow cytometry, immunofluorescence, and bulk RNAseq. Results The proportions of CD3+ T cells, monocytes, and macrophages were significantly increased in the brains of the dirty tau-P301S mice compared to their clean tau-P301S counterparts. The brains of the dirty tau-P301S mice also showed an increase in the proportion of CD8+ T cells, specifically effector differentiated (CD62L-CD44+) CD8+ T cells. The proportion of activated (CD11c+) microglia was increased in tau-P301S mice but unaffected by dirty status. Conclusion Disease-associated infiltration of adaptive immune cells into the brain is amplified by dirty status without grossly affecting microglial activation. Given the increasingly recognized role of T cells in Alzheimer’s disease pathogenesis, our results suggest that more immune educated models might better represent the role of T cells in neurodegenerative disease. Funding Source Mayo Clinic and The Translational Genomics Research Institute Topic Categories Neuroimmunology (NEUR)

Abstract Introduction The H-2Db class I restricted CD8 T cell response is critical for clearance of neurotropic Theiler’s virus encephalomyelitis virus (TMEV) infection. However, the key central nervous system cell types required to present H-2Db for CD8 T cell trafficking and expansion in the brain are not known. Mural cells are a critical cellular component of the neurovascular unit for maintaining vascular integrity which also express MHC class I molecules. However, the importance of mural cell antigen-restricted engagement by CD8 T cells has not been investigated. Methods To determine the function of mural cell MHC Class I antigen presentation, we crossed the Pdgfrβ-creERT2 mouse to our novel H-2Db LoxP mouse developed by our laboratory. This transgenic mouse approach enabled us to target mural cells during neuroinflammation. Results We observed robust knockdown of H-2Db on mural cells during acute TMEV infection. Conditional H-2Db knockdown in mural cells resulted in increased brain infiltration of CD8 T cells specific to the immunodominant Db:VP2 121-130 epitope of TMEV, demonstrating an important role of mural cells for immune cell recruitment. Conclusion To our knowledge, this is the first study demonstrating MHC class I antigen presentation by mural cells impacts CD8 T cell recruitment during neuroinflammation. Funding Source R01-NS103212, T32-AI170478 Topic Categories Neuroimmunology (NEUR)

Abstract Introduction T cell activation is a dynamic process governed by the strength and duration of antigen recognition via the T cell receptor (TCR). The timing of in vivo TCR signaling— when and how strongly memory CD8+ T cells become reactivated in the inflamed brain following antigen exposure— is a fundamental mechanism that remains unclear. The Nr4a3-Tocky reporter (Tocky) mouse employs a fluorescent timer that shifts from blue to red after TCR-driven Nr4a3 activation, which allows researchers to track activation kinetics through two parameters: the Timer Angle (recency of T cell activation), and the Timer Intensity (strength of signaling). Methods To understand CD8+ T cell activation during this neuroinflammation, we generated memory CD8+ T cells by intracranial Theiler’s murine encephalomyelitis virus infection of these Tocky mice. After viral clearance, we reactivated memory CD8+ T cells by intravenously injecting their cognate antigen. Tissues were collected 0-72 hours post-injection and profiled by flow cytometry. An R pipeline was constructed to transform event-level flow data to quantify the TCR activation. Data were analyzed with a Metropolis—Hastings MCMC algorithm to model activation dynamics and estimate probabilistic transitions between biologically defined states (newly activated, persistent, arrested states). Results These empirical transition probabilities enabled Bayesian comparison of antigen-specific versus nonspecific CD8+ T cells. It was revealed that antigen-specific CD8+ T cells rapidly transition to a high-intensity activation state within 24 hours and maintain persistent signaling compared to nonspecific populations. Conclusion This establishes a biologically grounded, in vivo framework for modeling and comparing TCR signaling during neuroinflammation. Funding Source R01 - NS103212 Topic Categories Neuroimmunology (NEUR)

Background: Total kidney volume (TKV), a prognostic biomarker in ADPKD, is used to stratify high risk individuals. eGFR measures may carry significant error in ADPKD compared to measured GFR(mGFR). This retrospective study investigates the association between height adjusted TKV (htTKV) and eGFR derived from race-free CKD-EPI equations utilizing creatinine and cystatin C. Methods: eGFR was calculated using 3 race-free CKD-EPI formulas: creatinine-based (CKD-EPI creatinine), cystatin C (CKD-EPI cys), and creatinine-cystatin C (CKD-EPI creatinine-cystatin C) equations on 697 Mayo Clinic ADPKD patients. Correlations between eGFR and TKV measures were estimated and stratified by MIC class risk groups and CKD. Linear regression models were computed to predict ln(htTKV) from the 3 eGFR data sets. The eGFR measures were compared to iothalamate-based mGFR in a subset of patients (n=50). Results: A correlation between eGFR measures and htTKV (Pearson correlation r of -0.53 to -0.54), varied by MIC stratification. Pearson correlation was -0.47 to -0.48 for MIC 1A and 1B, -0.67 to -0.71 for MIC 1C, and -0.67 to -0.68 for MIC 1D and 1E. All equations were significantly associated with htTKV levels, with similar adjusted beta values (95% CI) of -0.15 (-0.17 to -0.13), -0.14 (-0.16 to -0.12), -0.15 (-0.16 to -0.13), for CKD-EPI creatinine, CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C, respectively. Compared to mGFR, the CKD-EPI creatinine-cystatin C equation was the least biased (mean -0.86 (95% CI: -3.09 to 1.37)) versus CKD-EPI creatinine (2.31 (-0.73 to 5.34)) or CKD-EPI cystatin C (-3.54 (-5.86 to -1.21)), and most precise, with 1-P30 of 16% (95% CI 7.2% to 29.1%), compared to 18% (8.6% to 31.4%) for CKD-EPI creatinine, or 20% (10.0% to 33.7%) for CKD-EPI cystatin C. Conclusion: A moderate correlation between eGFR and htTKV associated with MIC stratification. Associations between htTKV and all 3 CKD-EPI equations were similar. CKDEPIcrcys tended to be the least biased and most precise equation when compared to mGFR and may be a reasonable alternative.

Abstract Introduction The underlying immunopathogenesis of inflammatory arthritis (IA) immune-related adverse event (irAE) remains obscure. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA-irAE is unclear. Methods Here, we performed immunophenotyping of peripheral blood from IA-irAE patients, and compared them with seronegative RA patients, ICI-treated patients without irAE, and healthy controls. Results IA-irAE was marked with increased cytotoxic gene expression and metabolic activation in T cells, and reduced CXCR3 and CCR6 expression in CD4+ T cells. Contrary to seronegative RA, IA-irAE patients displayed no significant elevation in autoantibody levels or atypical CD11c+CD21⁻ B cells. IA-irAE was further characterized by elevated levels of IL-6, IL-12, and type I IFN, which correlated with the T cell activation phenotypes. Conclusion Altogether, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs. Funding Source National Institute of Arthritis and Musculoskeletal and Skin Diseases Mark E. and Mary A. Davis Initiative in Rheumatoid Arthritis Research Mayo Foundation for Medical Education and Research Topic Categories Basic Autoimmunity (BA)

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.