No abstract

EGFR inhibitors (EGFRi) are effective against -mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, We recently demonstrated that can arise during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like We have developed DTCs to EGFRi in-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink -mutant lung cancer tumors We demonstrate surviving-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early -mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both and Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy..

One month following injury, MDC is largely intact in patients with mTBI, but is impaired in patients with cmTBI and msevTBI. Impaired MDC is prevalent in acute TBI and is strongly related to injury severity.

Objective To develop cognitive models of financial capacity (FC) in patients with traumatic brain injury (TBI). Design Longitudinal design. Setting Inpatient brain injury rehabilitation unit. Participants 20 healthy controls, and 24 adults with moderate-to-severe TBI were assessed at baseline (30 days postinjury) and 6 months postinjury. Main Outcome Measures The Financial Capacity Instrument (FCI) and a neuropsychological test battery. Univariate correlation and multiple regression procedures were employed to develop cognitive models of FCI performance in the TBI group, at baseline and 6 month time follow-up. Results Three cognitive predictor models of FC were developed. At baseline, measures of mental arithmetic/working memory and immediate verbal memory predicted baseline FCI performance (R2=.72). At 6 month follow-up, measures of executive function and mental arithmetic/working memory predicted 6 month FCI performance (R2=.79), and a third model found that these two measures, at baseline predicted 6 month FCI performance (R2=.71). Conclusions Multiple cognitive functions are associated with initial impairment and partial recovery of FC in moderate-to-severe TBI patients. In particular, arithmetic, working memory, and executive function skills appear critical to recovery of FC in TBI. The study results represent an initial step towards developing a neurocognitive model of FC in patients with TBI.

Objective To investigate recovery of medical decision-making capacity (MDC) over six-months in persons with traumatic brain injury (TBI) stratified by injury severity. Design Longitudinal study comparing controls and TBI patients one month after injury (T1) and six-months after injury (T2). Setting Inpatient TBI rehabilitation unit and outpatient neurology department. Participants 60 controls and 91 patients with TBI stratified by injury severity: 27 mild (mTBI), 20 complicated mild (cmTBI), and 44 moderate/severe (msevTBI). Interventions Not applicable. Main Outcome Measures We used the Capacity to Consent to Treatment Instrument (CCTI) to evaluate MDC performance on five consent standards (expressing choice, reasonable choice, appreciation, reasoning, and understanding). We also assigned capacity impairment ratings on the consent standards to each TBI participant using cut-scores referenced to control performance. Results Control performance was stable across time on the consent standards. Patients with mTBI and cmTBI performed below controls on the understanding standard at T1 but not T2. Patients with msevTBI performed below controls on appreciation, reasoning, and understanding at T1 and on appreciation and understanding at T2, but showed substantial improvement over time. Conclusions Regardless of injury severity, all groups with TBI demonstrated baseline impairment of MDC with subsequent partial or full recovery of MDC over a six-month period. However, a sizeable proportion of individual TBI patients in each group continued to demonstrate capacity compromise at six-months post-injury. Clinically this finding suggests that individuals with TBI, regardless of injury severity, need continued monitoring regarding MDC for at least six-months after injury.