The feasibility of detecting mild dehydration by using autonomic responses to cognitive stress was studied. To induce cognitive stress, subjects (n = 17) performed the Stroop task, which comprised four minutes of rest and four minutes of test. Nine indices of autonomic control based on electrodermal activity (EDA) and pulse rate variability (PRV) were obtained during both the rest and test stages of the Stroop task. Measurements were taken on three consecutive days in which subjects were "wet" (not dehydrated) and "dry" (experiencing mild dehydration caused by fluid restriction). Nine approaches were tested for classification of "wet" and "dry" conditions:(1) linear (LDA) and (2) quadratic discriminant analysis (QDA), (3) logistic regression, (4) support vector machines (SVM) with cubic, (5) fine Gaussian kernel, (6) medium Gaussian kernel, (7) a k-nearest neighbor (KNN) classifier, (8) decision trees, and (9) subspace ensemble of KNN classifiers (SE-KNN). The classification models were tested for all possible combinations of the nine indices of autonomic nervous system control, and their performance was assessed by using leave-one-subject-out cross-validation. An overall accuracy of mild dehydration detection was 91.2% when using the cubic SE-KNN and indices obtained only at rest, and the accuracy was 91.2% when using the cubic SVM classifiers and indices obtained only at test. Accuracy was 86.8% when rest-to-test increments in the autonomic indices were used along with the KNN and QDA classifiers. In summary, measures of autonomic function based on EDA and PRV are suitable for detecting mild dehydration and could potentially be used for the noninvasive testing of dehydration.

Heart rate variability (HRV) and electrodermal activity (EDA) are useful tools for assessing the central and peripheral dynamics of the sympathetic nervous system and detecting the effects of numerous systemic diseases and life-challenging situations. However, the indices of HRV and EDA are highly influenced by mental stress, environmental conditions, body position, and other physiological conditions that introduce variability. In this paper, we assessed the five-day reproducibility of HRV and EDA measures of sympathetic control, for N = 20 subjects undergoing 70 • head-up tilt test (HUT) and Stroop task tests. We made the assessment in highly controlled conditions without environmental causes of variability, to have a good baseline understanding of the consistency of the various indices of HRV and EDA. Therefore, we assessed intra-subject variation (using the coefficient of variation, CV) and consistency (using the intra-class correlation coefficient, ICC) of the test-to-baseline differences produced by both tests on the studied measures. The low-frequency component of HRV (HRVLF), and its normalized variant was computed as HRV measures of sympathetic control. For EDA, the skin conductance level, frequency of non-specific skin conductance responses, spectral index (EDASympn), and time-varying index (TVSymp) were computed. TVSymp (ICC = 0.85) and HRV indices exhibited higher consistency during the HUT (ICC ≥ 0.8), compared to other EDA measures, and HRVLF was the least variable measure (CV = 85.4%). EDA indices exhibited higher consistency (except for the EDASympn) during the Stroop task (ICC ≥ 0.79) when compared to HRV, and TVSymp was the least variable measure (CV = 97.2%). Remarkably, TVSymp proved to be a reproducible measurement (low variation and high consistency) in both scenarios. These results are the necessary groundwork for studying the use of EDA and HRV in real-world conditions, as reproducibility of the indices has remarkable importance in clinical practice. INDEX TERMSAutonomic nervous system, electrodermal activity, heart rate variability, reproducibility, Stroop task, tilt table test.

KRAS is genomically altered in about one third of all human tumors. Due to its central role in oncogenesis, many attempts have been made in the last four decades to drug mutant KRAS, either directly or indirectly. Despite recent advances in targeting KRAS using small molecule inhibitors, the majority of KRAS alterations do not yet have an existing targeted therapy, and where inhibitors are available, resistance rapidly emerges. Thus, novel approaches to drugging KRAS are needed. Eliminating mutant KRAS using a targeted protein degradation approach may lead to superior efficacy relative to inhibiting the protein. KRAS PROTAC® degraders that selectively target the G12D mutant form of KRAS were identified and profiled in KRAS-dependent cancer models. In vitro, PROTAC degraders targeting the G12D mutant degrade KRAS with picomolar potency, robustly suppress MAPK and PI3K/AKT signaling, induce apoptosis, and have antiproliferative activity that is superior to known inhibitors. These molecules are selective for mutant KRAS G12D, neither degrading wild-type KRAS nor the related isoforms HRAS and NRAS. In vivo, these degraders can eliminate >95% of mutant KRAS from relevant xenograft models, induce apoptosis, and lead to tumor regression. Consistent with the extended pharmacodynamics often observed with PROTAC degraders, a single dose of a G12D PROTAC results in prolonged KRAS degradation and significant pERK suppression up to one week after administration. Combined, these data show that degrading mutant KRAS G12D in tumors is highly efficacious and may have advantages over inhibition, making it an exciting potential new approach for the treatment of KRAS mutant cancers. Citation Format: Kathryn Smith, Andrea Lopez-Arroyo, Jason Berk, Peter Hegan, Peter Nower, Samantha Tice, Aurelie Moutran, Jennifer Pizzano, Amanda Dowtin, Mark Bookbinder, Elizabeth Bortolon, Greg Cadelina, Fazlul Karim, Katie Digianantonio, Miklos Bekes, Jesus Medina. KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR09.