Citations

Abstract Background Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. Methods We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. Results ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. Conclusions This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

ABSTRACT Advanced chronic diseases, or multicomplexity in older adults presents unique challenges. Transthyretin cardiac amyloidosis (ATTR‐CA) is one such scenario where heart failure is a common presentation, and management remains challenging. We describe the challenges involved in the diagnosis of ATTR‐CA in older adults, which has implications on treatment options. We discuss the application of comprehensive geriatric assessment (CGA) and shared decision making (SDM) in the context of these challenges. Based on geriatric medicine principles, an innovative framework for applying SDM in ATTR‐CA patients is proposed, including consideration of the patient priorities care approach. The proposed framework emphasizes assessing functionality, frailty, and life expectancy to help categorize risk. This framework can be applied in various advanced chronic diseases or multicomplexity. Based on risk categorization, treatment burden, and alignment with values and preferences, management pathways are suggested for each risk category. Incorporating CGA and SDM, the proposed framework supports patient‐centered care, ensuring that clinical recommendations are tailored to each older adult's unique needs and goals. In ATTR‐CA, a collaboration between cardiology and geriatric medicine provides significant value in managing older adults. The need to prevent age‐related bias in clinical decision‐making exists across all health conditions, and the proposed framework allows for a thorough evaluation of multimorbidity, frailty, disability, and patient preferences. While ATTR‐CA is used as a prototype, this integrated approach can be applied across all health conditions and is essential for delivering holistic care, improving communication, and aligning treatment plans with patient values.

Abstract Here, we examine immune signaling pathways affecting the duration of primary nasopharyngeal colonization by Streptococcus pneumoniae ( Spn ), the first step in its pathogenesis. Spn colonization which lasts days to weeks in WT mice was persistent ( > 6 months) in the absence of IL-17RA-signaling. RNA-seq analysis confirmed the role of IL-17RA signaling in neutrophil-associated pathways. Rather than driving neutrophil specific chemokine expression, IL-17RA-signaling was required to replenish neutrophils in nasal tissue that were otherwise depleted during infection. Enhanced neutrophil trafficking correlated with IL-17RA-dependent expression of endothelial cell adhesion molecules that promote neutrophil trafficking from the circulation into nasal tissue. Persistent colonization was also observed in mice lacking IL-1R-signaling. Recognition of IL-1-family cytokines, however, was not necessary for the expression of IL-17A or neutrophil recruitment. Instead, IL-1R-signaling was associated with the activation of neutrophils in nasal tissue that displayed increased levels of the surface marker CD11b, an important receptor for the complement-opsonized phagocytosis of Spn . Our findings provide insight into the requirement for sustained neutrophil presence and activity to prevent persistent mucosal infection by a leading opportunistic mucosal pathogen. Author Summary Colonization of the upper airway by Streptococcus pneumoniae ( Spn ) is common and often asymptomatic, particularly in early life, yet prolonged colonization increases the risk of transmission and invasive disease. Despite its importance, the immune mechanisms that prevent long-term persistence of Spn in the upper airway are not fully understood. In this study, we investigated how two immune signaling pathways, the IL-17RA and IL-1R pathways, contribute to preventing persistent Spn colonization. Using a mouse model, we found that the IL-17RA pathway supports continued replenishment of neutrophils into nasal tissue by promoting expression of molecules that allow these cells to exit the bloodstream and enter the nasal tissue. In contrast, the IL-1R pathway activates neutrophils in a way that makes them more effective at clearing Spn . Loss of either pathway resulted in persistent Spn colonization, with an additive effect seen when both pathways were removed. Collectively, our results highlight how two distinct immune pathways cooperate to control pneumococcal colonization by sustaining neutrophil recruitment and function.

Abstract INTRODUCTION The genetic basis of sporadic early‐onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late‐onset Alzheimer's disease (LOAD) polygenic risk in EOAD. METHODS A LOAD polygenic score (PGS) was calculated in the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. RESULTS Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset ( p = 0.106) or with cognitive performance ( p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal‐associated protein 25 (SNAP‐25) ( p = 2.3 × 10 −5 ). DISCUSSION While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. Highlights LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal‐associated protein 25 (SNAP‐25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

ABSTRACT Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS) 1,2 . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD) 5,6 , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing’s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.

TPS611 Background: GPC3 is an oncofetal protein expressed in up to 75% of hepatocellular carcinomas (HCCs) and associated with poor prognosis. Its selective expression in tumor and not in normal tissue makes it a promising target for radiopharmaceutical imaging and therapy (theranostics). The GPC3-selective diagnostic RYZ811 ([ 68 Ga]Ga-RAYZ-8009) and therapeutic α particle-emitting RYZ801 ([ 225 Ac]Ac-RAYZ-8009) are a theranostic pair. Previous studies show high uptake of RYZ811 in intrahepatic and extrahepatic HCCs, with low normal liver background uptake. In GPC3+ HCC mouse models, single administrations of RYZ801 significantly inhibited tumor growth. Methods: RYZ801-101 is a single-arm, open-label, phase 1/1b study of RYZ811 and RYZ801 in previously treated patients with GPC3+ unresectable HCC. The study has two parts: dose escalation (part 1) and dose expansion (part 2). Each part consists of two stages: RYZ811 imaging and RYZ801 treatment. The aim of imaging is to determine if RYZ811 safely and adequately identifies patients with GPC3+ tumors. The aim of treatment is to determine the safety, pharmacokinetics (PK), recommended phase 2 dose (RP2D; part 1), and preliminary antitumor activity (part 2) of RYZ801. Key eligibility criteria are: confirmed HCC; Barcelona Clinic Liver Cancer stage B or C; Child-Pugh A; ≥1 RECIST v1.1-measurable lesion (treatment stage); and disease progression after ≥1 systemic therapy in part 1 and 1 prior line in part 2. In part 1, approximately 60 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 30 of these will receive escalating doses of RYZ801 (2.6–5.5 MBq × 4 doses) in the treatment stage. In part 2, approximately 80 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 40 of these will receive RYZ801 at the RP2D in the treatment stage. Primary RYZ811 objectives are to assess the safety/tolerability and biodistribution of RYZ811. Secondary objectives are to determine absorbed doses (ADs) to organs and tissues and any association between RYZ811 uptake and RYZ801 efficacy. Primary RYZ801 objectives are to identify the RP2D and safety/tolerability of RYZ801. Secondary objectives are to assess PK, ADs to critical organs and tumors, and preliminary antitumor activity. Enrollment for Part 1 is ongoing in the USA. Clinical trial information: NCT06726161 .

Abstract Background The mechanisms of left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) with moderate septal hypertrophy (≤ 18 mm) remain uncertain with therapeutic implications. This study investigated the role of three-dimensional echocardiography (3DE)-derived myocardial mechanics in LVOTO. Methods We retrospectively analyzed 216 HCM patients with moderate septal hypertrophy, stratified into nonobstructive (n = 38), provokable LVOTO (n = 63), and resting LVOTO (n = 115). Transthoracic echocardiography assessed LV geometry, LVOT diameter, anterior mitral leaflet length, and papillary muscle abnormalities (via a composite SubMV score). 3DE-derived strain parameters, including global longitudinal (GLS), circumferential, radial, area (GAS) strain, twist, and torsion, were quantified. Determinants of LVOTO were evaluated using multivariate regression, restricted cubic splines (RCS), and receiver operating characteristic (ROC) analysis. Results Both LVOTO subgroups showed significantly augmented strain mechanics versus nonobstructive patients, greatest in resting LVOTO (p < 0.05); twist and torsion were the strongest discriminators (p < 0.001). Multivariate regression showed that, beyond LVOT diameter and SubMV score, torsion (B = 9.47), twist (B = 1.92), and GAS (B = 1.29) independently predicted provoked LVOT gradients (all p < 0.05); RCS demonstrated nonlinear twist/torsion–LVOTO relationships, with obstruction risk rising sharply above twist = 15° and torsion = 3°/cm, especially under provocation. Torsion discriminated provokable LVOTO achieving 81% specificity (cutoff 2.4°/cm, AUC = 0.72), outperforming all structural parameters. Integrating 3DE-derived mechanics with structural metrics improved diagnostic accuracy, especially in provokable LVOTO (AUC 0.84 vs. 0.76, DeLong p = 0.003). Conclusions In moderate-hypertrophy HCM, 3DE-derived strain mechanics, especially twist and torsion, independently determine LVOTO beyond structural narrowing, particularly under provocation, strengthening mechanistic insight and clinical applicability.

Abstract Background The tau PET imaging with 18F‐flortacipir (18F‐FTP) has focused interest in accurately tracking longitudinal tau changes in Alzheimer's disease [1]. Thus, minimizing variability is critical. Off‐target signal has the potential to complicate interpretation of tau‐PET imaging due to potential spillover or bleed‐in effects, with increased effects seen in later stages of Alzheimer's due to cerebral atrophy and proximity of off‐target areas to relevant cortical areas[2]. Previously, we demonstrated the effect of uptake period activity on 18F‐FTP signal. With increasing recent interest in demographic factors that may affect off‐target binding, we investigated the effect of age in extra‐cerebral off‐target signal in 18F‐FTP PET imaging. Method Standard 18F‐FTP PET protocol was performed in 330 participants. Two independent readers measured tau uptake in predetermined off‐target regions, including extraocular muscle, meninges, and occipital bone among others. Linear regression models assessed the relationship between participants’ age, sex, and tau uptake values (SUV and SUVr) (SUV = (Tissue radioactivity concentration / Injected dose) / Body weight & SUVr = SUV of target region/ SUV of reference region.) Result Sex had a significant effect on off‐target signal in most brain regions, with variable positive or negative correlation based on area. Notably, SUV in the eyeball‐retina, occipital bone, upper skull meninges all showed significant positive correlation with sex, with ‘male’ status generally associated with lower SUV. The greatest effect of sex was observed in superior skull meninges, occipital bone, and internal carotid artery ( p <0.001). Age showed minimally affected SUV and SUVr in off‐target regions. SUVr values show a significant correlation with SUV values of upper skull meninges in sex. Cognitive status did not significantly affect off‐target SUV. Conclusion We observed that sex significantly affected extra‐brain off‐target signal in 18F‐FTP PET imaging, while age has minimal effect, adding to previous evidence of off‐target binding within brain regions. Further evaluation is necessary to understand the age‐related effects on off‐target regions. As a result, the variability introduced by sex may pose challenges to studying tau accumulation.

Abstract Background In vivo biomarkers that can detect long‐term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p ‐tau217 as a potential biomarker for CTE p ‐tau pathology, and examined the concordance between plasma p ‐tau217 and Aβ pathology in an at‐risk for CTE sample. Method The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F‐florbetapir (Aβ+=SUVR≥1.10), and 18F‐flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p ‐tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post‐mortem tissue. ANCOVA examined group differences in p ‐tau217 (football vs controls; TES‐CTE no, TES‐CTE suggestive, TES‐CTE possible/probable). Multivariable regression models tested associations between p ‐tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4 . Result Sample characteristics are in Table 1. p ‐tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=‐0.217, p = 0.005). There were no group differences in Aβ‐PET SUVR. No differences were found across TES‐CTE certainty levels. In football players, higher p ‐tau217 was associated with higher Aβ‐PET SUVR (B=1.380, 95%CI[0.597‐2.155], p = 0.001) but not when Aβ+ ( n = 17) participants and those with kidney/liver disease ( n = 5) were excluded. Aβ+ participants had the highest p ‐tau217 (Figure 1). When compared against Aβ‐PET, several false Aβ‐positives (high p ‐tau217, Aβ‐) were identified, including one extreme outlier (assay related) and a cluster of Aβ‐ participants with p ‐tau217 between 0.60–1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p ‐tau217 outliers had autopsy‐confirmed CTE stage III (AD‐, Table 2). Of the remaining donors, all were AD‐ and four had CTE (stages II‐IV) with ptau217 between 0.125‐0.449. Conclusion Plasma p ‐tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at‐risk for CTE sample, p ‐tau217 and Aβ‐PET were associated at the group level. At the individual level, false Aβ‐positives (and negatives) existed, including Aβ‐ participants with high p ‐tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N‐terminal binding in p ‐tau assays.

Background: Institutions that participate in PCORnet ® transform their local electronic health record (EHR) data into the PCORnet ® Common Data Model (CDM), which is then used to generate data extracts for PCORnet ® Studies. PCORnet ® Studies can also include institutions that do not participate in PCORnet, and for these organizations, the cost of instantiating a PCORnet ® CDM can be prohibitive. Fast Health care Interoperability Resources (FHIR) provides an alternative method of obtaining EHR data. Objective: To determine whether data obtained through FHIR might be a viable study solution for those sites that do not participate in PCORnet. ® This mixed-methods project had 2 objectives: (1) survey sites participating in PCORnet on the availability of FHIR (FHIR survey); (2) compare the coverage of a FHIR-based data extract using REDCap with one from the PCORnet ® CDM across 3 sites (FHIR extract). Methods: (1) FHIR survey: A series of questions were asked about the use of FHIR in a production capacity. (2) FHIR extract: REDCap FHIR and PCORnet ® CDM extracts were created based on study variables from 2 prior PCORnet ® Studies. Data were extracted for 40 patients and concordance measures were computed between the 2 sources. Results: (1) FHIR survey: Of responding organizations, 73% (n=49) reported that FHIR was deployed in a production capacity. (2) FHIR extract: Results were highly variable. Cohen kappa ranged from 0.01 to 0.76 for certain diagnoses, 0.24 to 0.84 for laboratory results, and 0.1 to 0.87 for medications. Conclusions: Despite differences in data, certain studies may be well-suited for FHIR-based extracts.