Gradually increasing context-sensitivity shapes the development of children's verb marking: A corpus study.

There is substantial evidence that children's apparent omission of grammatical morphemes in utterances such as "She play tennis" and "Mummy eating" is in fact errors of commission in which contextually licensed unmarked forms encountered in the input are reproduced in a context-blind fashion. So how do children stop making such errors? In this study, we test the assumption that children's ability to recover from error is related to their developing sensitivity to longer-range dependencies. We use a pre-registered corpus analysis to explore the predictive value of different cues with regards to children's verb-marking errors and observe a developmental pattern consistent with this account. We look at context-independent cues (the identity of the specific verb being used) and at the relative value of context-dependent cues (the identity of the specific subject+verb sequence being used). We find that the only consistent effect across a group of 2- to 3-year-olds and a group of 3- to 4-year-olds is the relative frequency of unmarked forms of specific subject+verb sequences being used. The relative frequency of unmarked forms of the verb alone is predictive only in the younger age group. This is consistent with an account in which children recover from making errors by becoming progressively more sensitive to context, at first the immediately preceding lexical contexts (e.g., the subject that precedes the verb) and eventually more distant grammatical markers (e.g., the fronted auxiliary that precedes the subject in questions). RESEARCH HIGHLIGHTS: We provide a corpus analysis investigating input effects on young children's verb-marking errors (e.g., Mummy go) across development (between 2 and 4 years of age). We find evidence that these apparent errors of omission are in fact input-driven errors of commission that persist into the third year of life. We compare the relative effect on error rates of context-independent (e.g., verb) and context-dependent (e.g., subject+verb sequence) cues across developmental time. Our findings support the proposal that children recover from making verb-marking errors by becoming progressively more sensitive to preceding context.

Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours.

PURPOSE: PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study. PATIENTS AND METHODS: Tolerability and efficacy studies were performed in patient-derived xenograft(PDX) models of ovarian cancer. Clinical safety, tolerability, steady-state pharmacokinetics and preliminary efficacy of olaparib and onalespib were evaluated using a standard 3 + 3 dose-escalation design. RESULTS: Olaparib/onalespib exhibited anti-tumour activity against BRCA1-mutated PDX models with acquired PARPi resistance and PDX models with RB-pathway alterations(CDKN2A loss and CCNE1 overexpression). Phase 1 evaluation revealed that dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg were safe without dose-limiting toxicities. Coadministration of olaparib and onalespib did not appear to affect the steady-state pharmacokinetics of either agent. There were no objective responses, but disease stabilisation ≥24 weeks was observed in 7/22 (32%) evaluable patients including patients with BRCA-mutated ovarian cancers and acquired PARPi resistance and patients with tumours harbouring RB-pathway alterations. CONCLUSIONS: Combining onalespib and olaparib was feasible and demonstrated preliminary evidence of anti-tumour activity.

Suicidal ideation is associated with safety behavior usage among trauma-exposed individuals.

BACKGROUND: Long-standing theoretical perspectives on suicidal ideation (SI) have posited that SI arises, in part, as a way to obtain relief from intense emotional pain. Yet, little research has examined whether SI is linked with other relief-driven behaviors. The present study sought to provide preliminary support for the link between SI and relief-driven safety behavior usage, a commonly used strategy for managing distress among trauma-exposed individuals. METHODS: Trauma-exposed participants (n = 95) recruited for a larger study assessing mechanisms of posttraumatic stress disorder symptomology and completed a battery of self-report measures, including SI and their use of safety behaviors. Zero-inflated negative binomial regressions were utilized to examine the association of safety behavior usage with the presence/absence of SI (i.e., zero-inflation) and SI severity. RESULTS: In bivariate models, safety behaviors were associated with a greater likelihood of experiencing any SI and reporting more severe SI. When covariates were added to the model, safety behavior usage remained significantly and positively associated with SI severity. LIMITATIONS: The present study employed cross-sectional analyses of self-report data. Future research should use neurobehavioral tasks and intensive longitudinal data to test whether an underlying sensitivity to, or propensity to engage in, relief-driven behaviors contributes to SI. DISCUSSION: Among trauma-exposed individuals, those who more frequently engage in negatively reinforced safety behaviors also report more severe SI. These findings dovetail with theoretical foundations of suicide linking SI with relief-driven motivations and provide further support that a propensity to engage in relief-driven behaviors is associated with SI.

Combined aromatase, CDK4/6 and PI3K blockade using letrozole/abemaciclib/LY3023414 in endometrial cancer.

Several lines of preclinical evidence indicate that combining PI3K and CDK4/6 inhibitors may further enhance the efficacy of hormonal therapy by overcoming de novo and acquired resistance to PI3K and CDK4/6 blockade. We evaluated the combination of abemaciclib, letrozole and LY3023414 (an orally available, selective inhibitor of the class I PI3K isoforms and mTORC1/2) in recurrent endometrial cancer (EC). This study was terminated prematurely after 5 patients initiated protocol therapy due to discontinuation of further development of LY3023414. We report our findings from these patients, including one with recurrent endometrioid EC with AKT1, CTNNB1 and ESR1 hotspot mutations who had previously progressed through letrozole/everolimus and achieved a partial response to letrozole/abemaciclib/LY3023414.

Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses.

PURPOSE: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.

Investigating the Relationship between Fear of Failure and the Delivery of End-of-Life Care: A Questionnaire Study.

OBJECTIVE: To investigate whether fear of failure (FOF) influences a clinician's perception of how confident and comfortable they are in their delivery of end-of-life (EOL) care. METHODS: Cross-sectional questionnaire study with recruitment of physicians and nurses across two large NHS hospital trusts in the UK and national UK professional networks. A total of 104 physicians and 101 specialist nurses across 20 hospital specialities provided data that were analysed using a two-step hierarchical regression. RESULTS: The study validated the PFAI measure for use in medical contexts. Number of EOL conversations, gender, and role were shown to impact confidence and comfortableness with EOL care. Four FOF subscales did show a significant relationship with perceived delivery of EOL care. CONCLUSION: Aspects of FOF can be shown to negatively impact the clinician experience of delivering EOL care. CLINICAL IMPLICATIONS: Further study should explore how FOF develops, populations that are more susceptible, sustaining factors, and its impact on clinical care. Techniques developed to manage FOF in other populations can now be investigated in a medical population.

A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer.

PURPOSE: Estrogen receptor (ER)-positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/ß-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting. METHODS: We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months. RESULTS: At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common ≥ grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response (CTNNB1, KRAS, and CDKN2A mutations) or absence of response (TP53 mutations), which require independent validation. CONCLUSION: Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.

Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer.

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC. Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC. Design, Settings, and Participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies. Interventions: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects. Main Outcomes and Measures: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity. Results: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02912572.

The Impact of Interactive Shared Book Reading on Children's Language Skills: A Randomized Controlled Trial.

Purpose Research has indicated that interactive shared book reading can support a wide range of early language skills and that children who are read to regularly in the early years learn language faster, enter school with a larger vocabulary, and become more successful readers at school. Despite the large volume of research suggesting interactive shared reading is beneficial for language development, two fundamental issues remain outstanding: whether shared book reading interventions are equally effective (a) for children from all socioeconomic backgrounds and (b) for a range of language skills. Method To address these issues, we conducted a randomized controlled trial to investigate the effects of two 6-week interactive shared reading interventions on a range of language skills in children across the socioeconomic spectrum. One hundred and fifty children aged between 2;6 and 3;0 (years;months) were randomly assigned to one of three conditions: a pause reading, a dialogic reading, or an active shared reading control condition. Results The findings indicated that the interventions were effective at changing caregiver reading behaviors. However, the interventions did not boost children's language skills over and above the effect of an active reading control condition. There were also no effects of socioeconomic status. Conclusion This randomized controlled trial showed that caregivers from all socioeconomic backgrounds successfully adopted an interactive shared reading style. However, while the interventions were effective at increasing caregivers' use of interactive shared book reading behaviors, this did not have a significant impact on the children's language skills. The findings are discussed in terms of practical implications and future research. Supplemental Material https://doi.org/10.23641/asha.12420539.