Citations

Abstract RMC-6236 (daraxonrasib) is a novel multiselect RAS(ON) inhibitor under investigation for pancreatic ductal adenocarcinoma (PDAC) and other RAS-mutant cancers. This compound shares structural similarities with RMC-7977 and exhibits a conserved binding site and interaction pattern within the tri-complex formed between active RAS (RAS(ON)) proteins and cyclophilin A (CypA). Tumor Treating Fields (TTFields) are low-intensity, alternating electric fields that disrupt mitosis and have shown clinical benefit in solid tumors. The PANOVA-3 trial demonstrated that TTFields combined with gemcitabine plus nab-paclitaxel improved survival, pain control, and quality of life in locally advanced PDAC. Our previous work demonstrated that TTFields abrogate oncogenic KRAS pathway. We thus hypothesize a potential for increase in effectievness with the combination. In this study, the metastatic PDAC cell line AsPC-1 was treated with TTFields (150 kHz, 1.8 V/cm), RMC-6236 (15 nM; sub-IC50), or combination. A sub-IC50 concentration (15 nM) of RMC-6236 was selected based on MTS assay results, and subsequent experiments were performed at this dose. The MTS assay revealed that both TTFields and RMC-6236 independently reduced AsPC-1 cell viability, with a more pronounced reduction observed at 72 hours compared to 48 hours. RMC-6236 alone produced minimal effects at either 48 hours (85.82 ± 13.9%) or 72 hours (90.48 ± 15.4%) compared with control (100.0 ± 8.4%, 48 h; 100.0 ± 8.2%, 72 h). TTFields treatment significantly reduced viability to 74.42 ± 21.4% at 48 hours and 50.17 ± 26.5% at 72 hours. The combination treatment (TTFields + RMC-6236) further decreased viability to 63.8 ± 25.2% at 48 hours and 40.93 ± 18.1% at 72 hours, demonstrating synergistic cytotoxicity relative to monotherapy. Clonogenic assays were performed to evaluate cell survival fractions following treatment with RMC-6236, TTFields, and their combination. Cell migration was assessed using scratch assays, revealing that untreated cells exhibited a migration rate of 91.49 ± 0.85%, RMC-6236-treated cells showed 89.48 ± 1.3%, TTFields alone reduced migration to 61.33 ± 16.3%, and combination treatment markedly suppressed migration to 24.6 ± 22.13% . For every case we were compared with 72h cell migration rate with 0 h migration rate. These findings indicate that TTFields alone significantly impair cellular motility, while their combination with RMC-6236 results in a profound anti-migratory effect, substantially inhibiting wound closure. Additionally, western blot analysis was performed to assess changes in KRAS protein expression, a key PDAC biomarker. Overall, our results demonstrate that the combination of TTFields and RMC-6236 significantly inhibits PDAC cell growth, migration, and survival at sub-IC50 concentrations, suggesting a promising alternative therapeutic approach for PDAC management. Citation Format: Ishita Saha, Santanu Bhattacharya, Debabrata Mukhopadhyay, Hani M. Babiker. Synergistic antitumor activity of tumor-treating fields and multiselect-RAS (ON) inhibitor RMC-6236 in pancreatic ductal adenocarcinoma [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 4478.

Abstract Background: Spatial cellular ecosystems in the tumor microenvironment (TME) form dynamic signaling hubs that critically influence cancer disease progression and response to therapy, including response to immune checkpoint inhibitors (ICIs). However, tumor sampling bias and the impracticality of acquiring serial tumor biopsies have made it challenging to profile the TME clinically. To address this challenge, we developed Liquid EcoTyper, a multi-analyte AI framework to quantify TME spatial cellular ecosystems—termed spatial ecotypes (SEs)—noninvasively from cell-free DNA (cfDNA) methylation data. Methods: In previous work, we discovered nine spatial ecotypes, including SEs associated with ICI response (e.g., SE7 with benefit, SE4 with resistance), and quantified them from 1,249 bulk tumor RNA-seq profiles of melanoma, non-small cell lung cancer (NSCLC), and bladder cancer (BC) patients (Cancer Res (2025) 85 (8_Supplement_1): 153). Here we trained Liquid EcoTyper, an interpretable deep learning model, to transfer SE profiling to cell-free DNA using CpG methylation profiles. Performance was quantified using simulated and real data, including methylation profiles (EM-seq) of plasma cfDNA paired with tumor biopsy-derived SE levels determined by EM-seq (n=20 pairs) or 10x Visium (n=15 pairs). Clinical outcome prediction was evaluated using pretreatment plasma from patients treated with ICI alone (n=78 melanoma pts), chemotherapy and ICI (n=25 NSCLC pts), and enfortumab vedotin and ICI (n=10 localized muscle-invasive BC (MIBC) pts). Tumor mutational burden (TMB), tumor PD-L1, or circulating tumor DNA (ctDNA) were profiled as a comparator where possible. Results: We observed striking concordance between plasma-derived SE levels and tumor biopsy-confirmed SE levels from the same patients, demonstrating that liquid biopsy analysis of cfDNA methylomes can recapitulate TME spatial biology. Underscoring specificity, no reliable SE signal was detectable from peripheral blood mononuclear cells. In pre-ICI plasma, liquid SE levels were significantly associated with ICI-based response (SE7) versus resistance (SE4) in patients with melanoma, NSCLC, and MIBC, with a mean cross-cancer area under the curve (AUC) of 0.87 for SE7 (range 0.8-0.97) and 0.81 for SE4 (range 0.76-0.85)—far surpassing TMB, tumor PD-L1, and ctDNA in evaluable patients, both in binary analyses of response and multivariable models of survival. Our results also showed potential to predict pathologic complete response in the neoadjuvant setting. Conclusion: Liquid EcoTyper is a scalable noninvasive AI-based framework for spatiotemporal assessment of the TME. By enabling TME-informed risk stratification without surgical biopsies, Liquid EcoTyper has potential to enable more precise and actionable decision making in patients with solid tumors. Citation Format: Erin L. Brown, Wubing Zhang, Abul Usmani, Noah Earland, Ayesha Hashmi, Chibuzor Olelewe, Anushka Viswanathan, Pradeep S. Chauhan, Minji Kang, Chloé B. Steen, Hyun Soo Jeon, Susanna Avagyan, Irfan Alahi, Nicholas P. Semenkovich, Matteo Bergsagel, Janella C. Schwab, Chloe M. Sachs, Faridi Qaium, Peter K. Harris, Antonella Bacchiocchi, Qingyuan Cai, Andrew J. Gentles, Rondell P. Graham, Peter C. Lucas, Ryan C. Fields, Jacob J. Orme, Aaron S. Mansfield, Mario Sznol, Ruth Halaban, David Y. Chen, Aaron M. Newman, Aadel A. Chaudhuri. Liquid biopsy profiling of the tumor microenvironment to determine response to immunotherapy regimens across solid tumors [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 94.

Objective: To evaluate the current literature on the role of collagen peptide supplementation in bone health, focusing on changes in bone turnover markers (BTMs) and bone mineral density (BMD). Data Sources: A search was conducted following PRISMA guidelines in the databases Academic Search Premier, APA PsychInfo, CINAHL Plus, GreenFILE, MEDLINE, and SPORTDiscus. Keywords included “collagen supplementation,” “bone turnover,” and “bone structure.” Studies published between January 2000 and March 2024 were included if they involved human subjects, oral collagen supplementation, and skeletal-related outcomes (BTMs or BMD). Risk of bias was assessed using the modified Physiotherapy Evidence Database (PEDro) scale. Main Results: Fifteen studies met the inclusion criteria. Collagen supplementation was associated with improvements in BTMs such as procollagen type I N-terminal propeptide and C-terminal telopeptide of type I collagen, as well as increases in BMD at whole body, femoral neck, and lumbar spine sites, particularly in postmenopausal women. However, neutral findings and substantial heterogeneity in study design, population characteristics, and dosing protocols were also observed. Conclusions: Collagen supplementation shows promise for supporting bone health, particularly in postmenopausal women, but the evidence remains inconsistent. Future research should address these gaps by focusing on premenopausal populations, standardizing dosing protocols, and exploring broader orthopedic applications, such as reducing stress fractures and enhancing recovery from musculoskeletal injuries.

Abstract INTRODUCTION Visual perceptual difficulties occur in dementia with Lewy bodies (DLB). Normative data and cut scores for DLB and mild cognitive impairment with Lewy bodies (MCI‐LB) are needed for the 20‐item Noise Pareidolia Task. METHODS Participants included 344 cognitively unimpaired (CU), 112 DLB, and 105 MCI‐LB. Cumulative percentile ranking was used for normative classification. Receiver operating characteristic analyses, convergent validity, and associations with visual hallucinations (VH) were assessed. RESULTS In CU participants, a perfect score was average, one error was low average, and two or more errors fell below average. A cut score of one or more errors optimally distinguished CU participants from DLB (Total score area under the curve [AUC]: 0.82, Noise score AUC: 0.77) and MCI‐LB (Total score AUC: 0.75, Noise score AUC: 0.74). A cut score of two or more errors lowered sensitivity but increased specificity to 94%. Performance was associated with VH in DLB, but not MCI‐LB. DISCUSSION Results establish normative data for the 20‐item Noise Pareidolia Task and support its use in DLB and MCI‐LB.

Abstract The purpose of the current study was to identify the influence of individual characteristics on differences in body fat percentage between air displacement plethysmography and dual-energy X-ray absorptiometry (change in body fat percentage) in 360 collegiate student-athletes. Body fat percentage was obtained from air displacement plethysmography and dual-energy X-ray absorptiometry. A 2 (sex)×3 (Brozek body fat percentage, Siri body fat percentage, and dual-energy x-ray absorptiometry body fat percentage) analysis of variance was used to evaluate the difference between the body fat percentages obtained from air displacement plethysmography and dual-energy x-ray absorptiometry in men and women. The agreement between air displacement plethysmography and dual-energy X-ray absorptiometry was evaluated via Bland–Altman plot and linear regression. Multiple linear regression was used to identify the influence of sex, race, height, and body mass on the change in body fat percentages. Dual-energy X-ray absorptiometry yielded greater body fat percentages in both men (4.8±2.8; p < 0.001) and women (2.2±2.9; p < 0.001) compared to air displacement plethysmography measurements. Proportional and systematic biases were observed between air displacement plethysmography and dual-energy X-ray absorptiometry. Race, height, and mass were significant predictors of the body fat percentage difference between air displacement plethysmography and dual-energy X-ray absorptiometry (R 2=0.445, p<0.001, and standard error of the estimate=2.527). The present study suggests that air displacement plethysmography underestimates body fat percentages when compared to dual-energy X-ray absorptiometry and this underestimation may not be the same for every athlete due to their individual characteristics.

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

Carbohydrate availability and caffeine ingestion have been shown to elicit improvements in performance independently of one another. The purpose of the study was to examine the effect of a carbohydrate + caffeine beverage on performance and perceived effort in soccer players. Forty-three collegiate women’s soccer athletes were recruited to participate during a single day of simulated match play, in which each team played once. Athletes consumed either a carbohydrate + caffeine (Experimental) beverage or a control (Control) beverage (flavored water) during half-time in a double-blind, placebo-controlled, randomized control trial design. Prior to and after each game, Ratings of Perceived Exertion (RPE) and blood glucose levels were assessed. Heart rate, training impulse (TRIMP), total distance covered, high-speed distance, and velocity were recorded. Blood glucose levels after the match simulation were positively associated with total distance (r = 0.434; p = 0.01), distance per minute (r = 0.439; p < 0.01), average velocity (r = 0.438; p = 0.01), and TRIMP (r = 0.404; p = 0.018) during the second half. There was a significant main effect for half regarding blood glucose (p < 0.001), total distance (p < 0.001), high-speed distance (p < 0.001), and TRIMP (p = 0.046). There was a significant half × condition effect for blood glucose (p = 0.05). Pairwise comparisons indicated the Experimental beverage condition resulted in a +27 mg/dL (95% CI: −3.6, 58.8) difference compared to the Control beverage following the 2nd Half. In the current study, consumption of the carbohydrate + caffeine beverage during half-time resulted in higher blood glucose levels post-game compared to placebo; however, the experimental beverage did not influence the total distance covered, average velocities, average heart rate, or TRIMP values during the second half of simulated match play.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.