Citations

Abstract INTRODUCTION We examined when Alzheimer's disease biomarkers become informative by identifying age‐related breakpoints with slope‐changing trajectories. METHODS In 2082 Mayo Clinic Study of Aging participants, we modeled plasma amyloid beta (Aβ)42/40, phosphorylated tau (p‐tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid/tau positron emission tomography (PET), hippocampal volume (HVa), and global cognition. Generalized additive models described age trends; Davies' test and piecewise linear regression estimated breakpoints. A C2N subsample ( n = 462) provided mass‐spectrometry plasma markers (p‐tau181, p‐tau217, their ratios, Aβ42/40). RESULTS In the full cohort, Aβ42/40, HVa, and cognition declined with age; p‐tau181, NfL, GFAP, and amyloid/tau PET increased. We observed single breakpoints (years, 95% CI): GFAP 68.1 (63.5–71.8), NfL 70.7 (65.9–75.6), p‐tau181 67.2 (60.3–70.3), amyloid PET 62.3 (56.2–69.3), HVa 68.1 (63.1–71.9), cognition 59.8 (55.4–66.0); tau PET showed none. In the mass‐spectrometry subset, p‐tau217 and p‐tau181 broke at 72.6; their ratios and Aβ42/40 showed no breakpoints. DISCUSSION Breakpoints cluster near late midlife, suggesting windows for screening and monitoring.

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with marked molecular heterogeneity, limited systemic treatment options, and poor prognosis. Chemoresistance and KRAS mutations remain major therapeutic challenges. Dysregulation of the Hippo pathway, particularly YAP/TAZ hyperactivation, drives CCA progression and resistance. TEAD, the essential transcriptional partner of YAP/TAZ, represents a promising target. IAG933 is a novel oral pan-TEAD inhibitor designed to disrupt YAP/TAZ-TEAD interactions. RMC-6236, a pan-KRAS inhibitor, has also gained attention. Combined TEAD and KRAS inhibition may overcome resistance and improve efficacy in CCA. Methods: We evaluated IAG933 in human (HuCCT1, RBE) and murine (SB1, FAC) CCA cell lines. Cells were treated with IAG933 alone or in combination with GemCis or RMC-6236. Cell viability assays were used to determine IC50 values and calculate combination indexes (CI). TEAD activity was assessed by luciferase reporter and qRT-PCR of YAP/TAZ target genes (CTGF, CYR61, NUAK2). Transcriptomic alterations were analyzed by RNA sequencing. In vivo efficacy was evaluated in syngeneic orthotopic and patient-derived xenograft (PDX) models. Results: IAG933 suppressed TEAD-dependent transcription (IC50 ≈ 500 nM) and downregulated YAP/TAZ target genes. Combination with GemCis or RMC-6236 produced synergistic effects (CI < 1) in all CCA lines. Transcriptomic analysis revealed activation of oxidative stress response pathways, particularly SOD2 upregulation. MitoSOX staining confirmed increased mitochondrial ROS after treatment. In vivo, IAG933 monotherapy suppressed tumor growth similarly to GemCis. Dual TEAD and KRAS inhibition achieved marked tumor regression and significantly delayed tumor regrowth after treatment cessation in KRAS-mutant PDX models. Conclusion: IAG933 effectively suppresses YAP/TAZ-TEAD signaling and inhibits CCA growth. While the combination with GemCis showed limited additional benefit due to strong single-agent efficacy, synergy with RMC-6236 produced durable antitumor effects, particularly in run-out studies, delaying regrowth in KRAS-mutant models. These findings highlight IAG933 as a promising therapeutic candidate targeting the Hippo-TEAD pathway, with potential benefit in KRAS-mutant CCA. Citation Format: Hidemi Nishi,Erik Jessen,Danielle M. Carlson,Amro M. Abdelrahman,Enis H. Ozmert,J. Pedro Fincatto Safi,Brandon A. Wilbanks,Shelby K. Yee,Jack W. Sample,Nathan W. Werneburg,Rory L. Smoot. TEAD inhibition by IAG933 as a novel therapeutic strategy for cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3081.

Abstract Introduction: Src Family Kinases (SFKs) have a crucial role in tumor proliferation, survival, and metastasis. NXP900 is a highly selective SFK inhibitor with a novel mechanism of action that locks SFKs in a closed, inhibited conformation, providing sustained suppression of catalytic and non-catalytic functions, which is distinct from other SFK inhibitors like dasatinib. A phase I clinical trial of NXP900 in patients with advanced solid tumors is ongoing. Our preclinical studies showed therapeutic efficacy of NXP900 in cholangiocarcinoma (CCA) through decreased YAP, RAF-MAP and PI3K-AKT signaling. Multiomic profiling (RNA-seq, proteomics, phosphoproteomics) of CCA patient-derived xenografts implicated AKT pathway activation in primary NXP900 resistance. NXP900-resistant CCA cell lines generated via prolonged sublethal dose escalation showed a strong IL13RA2-AKT signature on multiomic analysis. Thus, we hypothesized that IL13RA2-AKT signaling was a mechanism of NXP900 resistance. We aimed to define this mechanism and demonstrate that the combinatorial targeting of IL13RA2 or AKT resensitizes to NXP900 treatment. Methods: HuCCT1 or HuCCT1-Resisant (HuCCT1-R) cells were injected bilaterally into the flanks of NOD/SCID mice and were allowed to grow for 3 months prior to tumor collection and analysis. Tumor engraftment and growth between HuCCT1 and HuCCT1-R groups were compared. To delineate the mechanisms for acquired NXP900 resistance, in-vitro treatment studies were performed using siRNAs targeting IL13RA2 as well as combination treatment with capivasertib, a pan-AKT inhibitor. Results: The HuCCT1-R cell line exhibited a higher rate of tumor engraftment and formed significantly larger tumors compared to the parental HuCCT1 cell line, indicating enhanced tumorigenic potential associated with acquired resistance. Silencing of IL13RA2 in HuCCT1-R cells resulted in pronounced reduction of cell proliferation and partially restored sensitivity to NXP900 treatment. Immunoblot analysis demonstrated a corresponding reduction in phosphorylated AKT (Thr308), consistent with suppression of downstream PI3K-AKT signaling. Furthermore, combination treatment of HuCCT1-R cells with the AKT inhibitor capivasertib, and NXP900 led to a significant increase in cell death and a greater inhibition in cell proliferation compared to either agent alone, indicating enhanced responsiveness and improved therapeutic efficacy. Conclusion: These findings confirm the central role of IL13RA2 signaling and the PI3K-AKT pathway in mediating acquired resistance to NXP900, consistent with our previous multiomics analysis. Importantly, this study identifies combination strategies that may be able to overcome NXP900 resistance, supporting the development of combinatorial approaches to restore therapeutic efficacy in resistant tumors. Citation Format: Shelby K. Yee, Hendrien Kuipers, Danielle M. Carlson, Jack W. Sample, Enis Ozmert, Hidemi Nishi, Erik Jessen, Dong-Gi Mun, Aushinie M. Abeynayake, Jennifer L. Tomlinson, Amro M. Abdelrahman, Nathan W. Werneburg, Binbin Li, Mitesh J. Borad, Mark J. Truty, Sumera I. Ilyas, Gregory J. Gores, Rory L. Smoot. Resistance to the SFK inhibitor NXP900 in cholangiocarcinoma is characterized by IL13RA2-AKT signaling and can be overcome by combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7124.

Abstract Background High-sensitivity cardiac troponin (hs-cTn) assays are recommended for the diagnosis of acute myocardial infarction. Here, we characterize the analytical performance of a next-generation hs-cTn assay, Elecsys® Troponin T hs Gen 6 (Roche Diagnostics International). Methods Surplus lithium-heparin plasma or serum samples from patients or healthy volunteers were run on Cobas® e 801, e 402, and Pro analyzers. Limits of blank (LoB), limits of detection (LoD), and limits of quantitation (LoQ) were determined according to CLSI EP17-A2, with target values of 1.0 and 1.5 ng/L for LoB/LoD and 3.0 ng/L (10% CV) and 1.5 ng/L (20% CV) for LoQ, respectively. Precision was measured, per CLSI EP17-A2, using 3 QC samples (approximately 4, 30, and 220 ng/L), 12 native samples, and 3 reagent lots. Linearity, per CLSI EP06-Ed2, was determined by diluting samples with cardiac troponin T (cTnT) concentration above the measuring range with a low/blank sample. Interference (per Glick) with endogenous and assay components at 5 cTnT concentrations was assessed. Results Measured values for LoB, LoD, and LoQ at 10% and 20% CV were 0.1 to 0.7 ng/L, 0.3 to 1.4 ng/L, 1.0 to 2.9 ng/L, and 0.4 to 1.2 ng/L, respectively. Repeatability CVs were 1.0 to 5.8% for mean cTnT concentrations of 2.6 to 9230 ng/L in lithium-heparin plasma. High precision was shown across lots, and linearity was observed across the measuring range (1.5 to 9500 ng/L, all Pearson's r = 1.00). No interferences were observed, specified up to ≤1000 mg/dL hemoglobin, ≤50 mg/dL [≤855 µmol/L] icterus/bilirubin, and ≤1200 ng/mL biotin. Conclusions The analytical performance characterization of the assay demonstrated high sensitivity, high precision at the low end and across the measuring range, and resistance to interference.

Transactive response DNA-binding protein of 43 kDa (TDP-43) type-A is associated with frontotemporal lobar degeneration (FTLD). In primary age-related tauopathy (PART), TDP-type-α displays similar features to FTLD-TDP type-A. We compared antemortem MRI volumes of amygdala nuclei and hippocampal subfields between 16 PART-TDP-α and 12 FTLD-TDP-A autopsy-confirmed cases. Hippocampal tail and CA1 body volumes were smaller in PART-TDP-α group, which also had smaller lateral and central amygdala nuclei compared to FTLD-TDP-A group, but differences were non-significant after FDR correction. There is no evidence suggesting that TDP-43 type-A in FTLD affects hippocampal and amygdala volume loss differently than TDP-43 type-α in PART.

Background TAR DNA-binding protein 43 (TDP-43) proteinopathy contributes to Alzheimer's disease progression, but diagnosis remains autopsy-dependent. Objective This study aimed to develop a predictive model using FDG-PET imaging to identify brain regions associated with TDP-43 pathology in vivo. Methods Penalized logistic regression analyzed data from 294 participants and a subset of 159 with Braak and Thal ≥4. Features included FDG standard uptake value ratios (SUVRs) from 123 brain regions and age. Participants were split into training (90%) and testing (10%) datasets, with significant predictors identified by non-zero coefficients at optimal lambda. Results The model achieved 68% accuracy (AUC = 0.70) in 294 participants, highlighting the middle temporal gyrus, parahippocampal gyrus, and hippocampus. In the subset (n = 159), accuracy was 65% (AUC = 0.71), with the medial amygdala and precentral gyrus as key predictors of TDP-43 pathology. Conclusions This study suggests a moderate predictive accuracy of FDG-PET to identify brain regions associated with Alzheimer's disease-related TDP-43 proteinopathy.

Abstract Background The number of arthroplasty procedures and infection-related complications, including prosthetic joint infections (PJIs) and surgical site infections (SSIs), continues to rise. Although current guidelines recommend cefazolin or cefuroxime as the first-line perioperative prophylactic antibiotic, substitutions with non-cephalosporins remain common, especially among patients with reported β-lactam allergies. These substitutions may increase infection risk and healthcare costs. Evidence comparing outcomes across antibiotic classes remains variable. Methods We conducted a systematic review and meta-analysis of studies comparing single-agent cephalosporin versus single-agent non-cephalosporin prophylaxis in adults undergoing primary arthroplasty. Cochrane, Embase, Medline, Scopus, and Web of Science were searched from database inception through January 2025. Random-effect or fixed-effect models were used to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Subgroup analyses stratified results by cephalosporin type, study era, and risk of bias. Results Twenty-three studies (7 randomized controlled trials and 16 observational studies) were included, encompassing 191 527 arthroplasties in the cephalosporin arm and 20 058 in the non-cephalosporin arm. The odds of PJI were lower with cephalosporins (OR 0.59; 95% CI, .46–.75). No overall difference was observed for SSI (OR 0.70; 95% CI, .36–1.36), though post-2013 studies and the cefazolin subgroup demonstrated a significant protective effect. Randomized trial estimates were limited and heterogeneous and did not reach statistical significance. Certainty of evidence was graded as moderate. Conclusions Cephalosporins, particularly cefazolin or cefuroxime, remain the preferred prophylactic agents for primary arthroplasty. This quantitative synthesis reinforces their protective association against prosthetic joint infection and supports adherence to guideline-endorsed prophylaxis.

Abstract Advances in biomarker technology, digital cognitive assessments, and amyloid‐targeting therapies have redefined the opportunities for accurate and early diagnosis and care of Alzheimer's disease (AD). These advances also create new possibilities for intervention before the onset of cognitive impairment. This paradigm shift has increased the focus on Stages 1 and 2 of AD, in which individuals are cognitively unimpaired but exhibit biological evidence of disease. While early identification of AD offers an opportunity to intervene early to delay progression and preserve quality of life, it also presents complex challenges related to communicating diagnostic results to patients and their families, contextualizing the cost effectiveness of early diagnosis and treatment, and implementation of and equitable access to treatments. Recent, successfully enrolled, preclinical AD trials highlight the complex strategies required to identify asymptomatic, biomarker‐positive individuals on a large scale, and demonstrate critical knowledge gaps in inclusion, follow‐up, and long‐term outcome measurement. The Spring 2025 Alzheimer's Association Research Roundtable (AARR) meeting brought together academics, clinicians, industry, and regulatory leaders to exchange perspectives on current challenges, key learnings, and potential strategies for identifying and treating individuals in very early stages of AD, effectively and safely. This paper presents key takeaways from the Spring 2025 AARR meeting. Highlights New criteria for Alzheimer's disease (AD) enable early identification of AD pathology. Blood tests and digital cognitive assessment tools may facilitate early and personalized care. Plasma biomarkers may be scalable in clinical settings but need confirmation or follow‐up assessments in those individuals with equivocal results. Early therapy shows best results in people with lower initial amyloid and tau burden.