Experiences of Older Adults Using Smart Home Technology in a Senior Living Community.

Researchers from a University partnered with a senior housing organization and a technology provider to study the implementation of smart home technologies for seniors living independently. Smart home technologies included in home motion and pressure sensors and an Amazon Echo device. Older adults who received the technology and their designated family members were interviewed to ascertain the impact of the technology on the daily activities and communication

Kinase-Impaired BTK Mutations Are Susceptible to Clinical-Stage BTK and IKZF1/3 Degrader NX-2127

INTRODUCTION: Bruton’s tyrosine kinase (BTK) is a nonreceptor kinase in the B cell receptor (BCR) signaling cascade critical for B cell survival. As such, chronic lymphocytic leukemia (CLL) and other B cell cancers are sensitive to inhibition of BTK. Covalent and noncovalent inhibitors of BTK have revolutionized the treatment of these cancers. Therefore, understanding mechanisms by which acquired mutation in BTK confer drug resistance and developing new therapies to overcome resistance are critically important. RATIONALE: We recently discovered BTK mutations that confer resistance across covalent and noncovalent BTK inhibitors. In this study, we found that a group of these mutants impair BTK kinase activity despite still enabling downstream BCR signaling. We therefore set out to understand the nonenzymatic functions of BTK and explored targeted protein degradation to overcome the oncogenic scaffold function of mutant BTK. This effort included evaluation of BTK degradation in patients with CLL treated in a phase 1 clinical trial of NX-2127, a first-in-class BTK degrader (NCT04830137). RESULTS: BTK enzymatic activity assays revealed that drug resistance mutations in BTK fall into two distinct groups: kinase proficient and kinase impaired. Immunoprecipitation mass spectrometry of kinase-impaired BTK L528W (Leu528→Trp) revealed a scaffold function of BTK with downstream signaling and survival dependent on surrogate kinases that bind to kinase-impaired BTK proteoforms. To target the nonenzymatic functions of BTK, we developed NX-2127, a heterobifunctional molecule that engages the ubiquitin-proteasome system to simultaneously bind both BTK and the cereblon E3 ubiquitin ligase complex, inducing polyubiquitination and proteasome-dependent degradation of IKZF1/3 and all recurrent drug-resistant forms of mutant BTK. The activity of NX-2127 on BTK degradation was further demonstrated in patients with CLL treated in a phase 1 clinical trial of NX-2127, where \u3e80% BTK degradation was achieved and clinical responses were also seen in 79% of evaluable patients, independent of mutant BTK genotypes. CONCLUSION: We identified that BTK inhibitor resistance mutations fall into two distinct functional categories. Kinase-impaired BTK mutants disable BTK kinase activity while promoting physical interactions with other kinases to sustain downstream BCR signaling. This scaffold function of BTK was disrupted by NX-2127, a potent BTK degrader, which showed promising responses for patients with relapsed and refractory CLL, independently of mutant BTK functional category

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors

BackgroundCovalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood.MethodsWe performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors.ResultsAmong 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors.ConclusionsResistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.)

Data

This component contains the raw individual .txt files outputted and time stamped after completing the experiment

Software

This component contains the LiveCode source file (version 9.0.2) for presenting the sequences and materials to participants and collecting their responses. LiveCode’s Community Edition, is a free open source object-oriented, cross-platform, natural language rapid development environment that can be used for programming local (LiveCode) and web-based (HTML5) experiments. LiveCode is based on the Transcript programming language (a high-level xTalk scripting language like HyperCard’s HyperTalk), and is a great stepping stone to learning Javascript and Python. It is fit for developing experiments that require fine-grained control, complex sequencing, and heavy back-end processing. You can download LiveCode for PC, Linux or Mac at: https://downloads.livecode.com/livecode. You can run this experiment on your own computer by installing the appropriate version of LiveCode Community, and downloading the zip file. Note, however, that the “images” file is missing, which you’ll need for the experiment to run properly. Please contact Jason Tangen ([email protected]). If you have permission to use these images, he’ll send you a link to the images we used in this project. Once you get the “images” folder, just put it inside the main experiment folder, which can be stored anywhere on your machine. But the file structure within this folder needs to be preserved to run the experiment, as the script is reading in the participant sequences, images, and instructions on the fly from the same location as the source file

Materials

The fingerprint images we used in this project were sourced from the FIBR database (see Tear, Thompson, & Tangen, 2010). Please contact Jason Tangen ([email protected]) for permission to use these images, and he’ll send you a link to the images we used in this project

Sequences

This component contains the full set of 64 pre-generated participant sequences as unique .txt files that are read into the experiment software (see Software component for this project)

Analyses

This component includes our complete data analytic pipeline: from raw individual .txt files to final R Markdown plots and analyses. The “analysis” folder contains data files (.txt) for 12 simulated novice participants and 12 simulated expert participants with pseudorandomly generated response data—these are used to test out the experimental analysis script, and model the null (e.g., what we’d expect to see in our data due to chance). Also included is a LiveCode data extraction tool for aggregating raw data from the individual .txt files, an R Markdown folder with source code, and a fully documented html file documenting all code, notes, plots and results of statistical analyses. A ‘final analysis’ folder will be uploaded here once data collection is completed and the human data have been run through this analytic pipeline

Data

This component contains the deidentified data for this experiment stored as .csv file

Expertise in locating information within fingerprints

In this experiment, we will test to see whether expert fingerprint examiners have better visual search abilities compared to novices with a class of stimuli they are familiar with. We will also test whether their superior performance disappears when the structural regularities of the stimuli are removed, or if asked to spot information that is non-diagnostic. We have conceptualised a fingerprint-like visual search task much like a Where's Wally puzzle that assesses how well participants can find points of correspondence (the find-the-fragment task). Participants will be asked to find a small fragment of print information (presented on the left) within a larger fingerprint image (presented on the right) as quickly as they can