The ability to effectively target mutated KRAS has remained elusive despite decades of research. The recent identification of KRAS G12C inhibitors has provided an effective treatment option for patients harboring this particular mutation and has also provided insight toward targeting other KRAS mutants, including KRAS G12D . MRTX1133 was identified via a structure-based drug design (SBDD) strategy as a potent, selective, and non-covalent KRAS G12D inhibitor directed at the switch II binding pocket. MRTX1133 demonstrated a high-affinity interaction with KRAS G12D with KD or IC50 values each determined at ~0.2 pM or <2 nM using SPR direct binding or HTRF competition assays, respectively. MRTX1133 also demonstrated ~700-fold selectivity for KRAS G12D vs KRAS WT binding utilizing SPR. Interestingly, MRTX1133 demonstrated potent inhibition of active KRAS G12D using an HTRF effector interaction assay with a IC50 value of 9 nM. Insight toward the structural basis of binding of MRTX1133 to both the inactive GDP-bound and active GMPPCP-bound conformations of KRAS G12D is also provided by co-crystal structures. MRTX1133 demonstrated potent inhibition of ERK1/2 phosphorylation and cell viability in KRAS G12D -mutant cell lines with median IC50 values of ~5 nM. Consistent with binding affinity determination in cell-free systems, MRTX1133 demonstrated >1000-fold selectivity for inhibition of ERK1/2 phosphorylation in KRAS G12Dmutant cell lines compared with KRAS WT cell lines. Dose-dependent inhibition of KRASmediated signal transduction was also observed in multiple KRAS G12D -mutant tumor models in vivo. MRTX1133 demonstrated marked tumor regression (>30%) in a subset of KRAS G12Dmutant cell line-and patient-derived xenograft (PDX) models, including 8 out of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models evaluated. Pharmacological studies and CRISPR-based screens demonstrated co-targeting KRAS G12D in concert with putative feedback or bypass pathways including EGFR and PI3Kα led to enhanced anti-tumor activity relative to targeting each individual protein. Together, these data indicate the feasibility of utilizing SBDD approaches to selectively target alternative KRAS mutant variants with non-covalent, highaffinity small molecules targeting either the active or inactive state of KRAS. In addition, these data illustrate the therapeutic susceptibility and broad dependence of KRAS G12D mutationpositive tumors, including PDAC, on KRAS for tumor cell growth and survival. SignificanceThe development of clinically active KRAS G12C -selective inhibitors represents a milestone achievement for the treatment of cancer; however, the discovery of additional KRAS-mutant selective inhibitors has remained elusive. MRTX1133 is a potent KRAS G12D -selective small molecule inhibitor, is active in vitro and in vivo, induces regression in multiple xenograft tumor models and demonstrates increased anti-tumor activity in rationally designed combinations. These data confirm KRAS G12D functions as an oncogenic driver, including in pancreat...

BACKGROUND/OBJECTIVES: Use of cannabis is increasing in a variety of populations in the United States; however, few investigations about how and for what reasons cannabis is used in older populations exist. DESIGN: Anonymous survey. SETTING: Geriatrics clinic. PARTICIPANTS: A total of 568 adults 65 years and older. INTERVENTION: Not applicable. MEASUREMENTS: Survey assessing characteristics of cannabis use. RESULTS: Approximately 15% (N = 83) of survey responders reported using cannabis within the past 3 years. Half (53%) reported using cannabis regularly on a daily or weekly basis, and reported using cannabidiol-only products (46%). The majority (78%) used cannabis for medical purposes only, with the most common targeted conditions/symptoms being pain/arthritis (73%), sleep disturbance (29%), anxiety (24%), and depression (17%). Just over three-quarters reported cannabis "somewhat" or "extremely" helpful in managing one of these conditions, with few adverse effects. Just over half obtained cannabis via a dispensary, and lotions (35%), tinctures (35%), and smoking (30%) were the most common administration forms. Most indicated family members (94%) knew about their cannabis use, about half reported their friends knew, and 41% reported their healthcare provider knowing. Sixty-one percent used cannabis for the first time as older adults (aged ≥61 years), and these users overall engaged in less risky use patterns (e.g., more likely to use for medical purposes, less likely to consume via smoking). CONCLUSION: Most older adults in the sample initiated cannabis use after the age of 60 years and used it primarily for medical purposes to treat pain, sleep disturbance, anxiety, and/or depression. Cannabis use by older adults is likely to increase due to medical need, favorable legalization, and attitudes.

Voice-based Intelligent Virtual Assistants (IVAs) promise to improve healthcare management and Quality of Life (QOL) by introducing the paradigm of hands-free and eye-free interactions. However, there has been little understanding regarding the challenges for designing such systems for older adults, especially when it comes to healthcare related tasks. To tackle this, we consider the processes of care delivery and QOL enhancements for older adults as a collaborative task between patients and providers. By interviewing 16 older adults living independently or semi-independently and 5 providers, we identified 12 barriers that older adults might encounter during daily routine and while managing health. We ultimately highlighted key design challenges and opportunities that might be introduced when integrating voice-based IVAs into the life of older adults. Our work will benefit practitioners who study and attempt to create full-fledged IVA-powered smart devices to deliver better care and support an increased QOL for aging populations. CCS CONCEPTS• Human-centered computing → Empirical studies in accessibility.

Ecological momentary assessment (EMA) is used to evaluate subjects' behaviors and moods in their natural environments, yet collecting real-time and self-report data with EMA is challenging due to user burden. Integrating voice into EMA data collection platforms through today's intelligent virtual assistants (IVAs) is promising due to hands-free and eye-free nature. However, efficiently managing conversations and EMAs is non-trivial and time consuming due to the ambiguity of the voice input. We approach this problem by rethinking the data modeling of EMA questions and what is needed to deploy them on voice-first user interfaces. We propose a unified metadata schema that models EMA questions and the necessary attributes to effectively and efficiently integrate voice as a new EMA modality. Our schema allows user experience researchers to write simple rules that can be rendered at run-time, instead of having to edit the source code. We showcase an example EMA survey implemented with our schema, which can run on multiple voice-only and voice-first devices. We believe that our work will accelerate the iterative prototyping and design process of real-world voice-based EMA data collection platforms.

The ability to effectively target mutated KRAS has remained elusive despite decades of research. The recent identification of KRASG12C inhibitors has provided an effective treatment option for patients harboring this particular mutation and has also provided insight toward targeting other KRAS mutants, including KRASG12D. MRTX1133 was identified via a structure-based drug design (SBDD) strategy as a potent, selective, and non-covalent KRASG12D inhibitor directed at the switch II binding pocket. MRTX1133 demonstrated a high-affinity interaction with KRASG12D with KD or IC50 values each determined at ~0.2 pM or <2 nM using SPR direct binding or HTRF competition assays, respectively. MRTX1133 also demonstrated ~700-fold selectivity for KRASG12D vs KRASWT binding utilizing SPR. Interestingly, MRTX1133 demonstrated potent inhibition of active KRASG12D using an HTRF effector interaction assay with a IC50 value of 9 nM. Insight toward the structural basis of binding of MRTX1133 to both the inactive GDP-bound and active GMPPCP-bound conformations of KRASG12D is also provided by co-crystal structures. MRTX1133 demonstrated potent inhibition of ERK1/2 phosphorylation and cell viability in KRASG12D-mutant cell lines with median IC50 values of ~5 nM. Consistent with binding affinity determination in cell-free systems, MRTX1133 demonstrated >1000-fold selectivity for inhibition of ERK1/2 phosphorylation in KRASG12D-mutant cell lines compared with KRASWT cell lines. Dose-dependent inhibition of KRAS-mediated signal transduction was also observed in multiple KRASG12D-mutant tumor models in vivo. MRTX1133 demonstrated marked tumor regression (>30%) in a subset of KRASG12D-mutant cell line- and patient-derived xenograft (PDX) models, including 8 out of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models evaluated. Pharmacological studies and CRISPR-based screens demonstrated co-targeting KRASG12D in concert with putative feedback or bypass pathways including EGFR and PI3Kα led to enhanced anti-tumor activity relative to targeting each individual protein. Together, these data indicate the feasibility of utilizing SBDD approaches to selectively target alternative KRAS mutant variants with non-covalent, high-affinity small molecules targeting either the active or inactive state of KRAS. In addition, these data illustrate the therapeutic susceptibility and broad dependence of KRASG12D mutation-positive tumors, including PDAC, on KRAS for tumor cell growth and survival.