Engagement Markers Research Articles

Abstract 2562: eIF4E modulators to address breast cancer resistance

Abstract ER+/HER2- advanced or metastatic breast cancers represents a large patient population served by CDK4/6 inhibitors combined with hormonal therapy as standard of care. As acquired resistance emerges, molecular profiling indicates about > 100 different mutations render resistance, creating challenges for treating physicians, patients, and the healthcare system broadly. The aim of our work is to maintain consolidation of this large patient population by developing targeted therapies to a key fundamental mechanism at the convergence of many oncogenic signaling pathways through which resistance arises. The regulation of CAP dependent protein translation is a central element in oncogenesis. One of a family of CAP binding proteins, eIF4E serves to anchor the m7GTP CAP of RNA into several protein complexes and regulates multiple aspects of mRNA processing such as nuclear export and ribosomal translation. Our efforts focused on simultaneously developing potent small molecule modulators of eIF4E and patient hypotheses through which to direct their initial clinical use. By aligning medicinal chemistry tools with patient directed pharmacology, we optimized our inhibitors to identify orally bioavailable, nM modulators of eIF4E. Biochemical assays demonstrated direct binding and allosteric modulation of eIF4E activity by PICRN941, along with Proximity Ligation Assays (PLA) demonstrating reduced eIF4E and 4G association in cells. Western analysis demonstrated that PICRN941 induced simultaneous and significant modulation of a number of key oncogenes that have been postulated to drive intrinsic or acquired resistance in response to standard of care including anti-estrogen treatment, CDK4/6 inhibitors or PI3K inhibitors combined with hormonal therapy, including MYC, CDK2, CDK4, CCND1 and eIF4E itself. Treatment of ER+ breast cancer cell lines including ZR-75-1, T47D, and ZR-75-30 with PICRN941 induced a dose dependent reduction in the levels of hyper-phosphorylated 4E-BP1 commensurate to increases in unphosphorylated 4E-BP1, and dose-dependent reduction in protein expression of Cyclin D1, CDK4, ER alpha, phosphorylated Rb and eIF4E. Reduced protein expression correlated with subsequent cell cycle arrest and apoptosis. We further studied our inhibitors in primary patient derived organoids in collaboration with the Hubrecht Institute, where we observed potent and complete responses in breast cancer organoids that represent patient populations where unmet needs remain high including PTEN and RB null organoid models. Markers of target engagement correlated well with organoid model sensitivity, including Cyclin D1 responses. Our findings suggest that our allosteric eIF4E modulators may provide a unique and efficient therapeutic approach to address multiple resistance mechanisms across cancer patient populations, toward fulfilling the promise of this elusive target. Citation Format: Lisa Sturla, Bassil Dekky, Xuemei Zhang, Katherine S. Bowdish, Chris VanDeusen. eIF4E modulators to address breast cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2562.

A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).

3004 Background: The highly potent MDM2–p53 antagonist BI 907828 showed antitumor efficacy in vivo, particularly in TP53 wild-type, MDM2-amplified de-differentiated LPS (DDLPS) patient-derived xenografts and syngeneic models. This phase I study (NCT03449381) is assessing BI 907828 monotherapy in patients with advanced solid tumors, including LPS. In Part A (dose escalation), patients received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. Based on previously reported results from Part A (LoRusso ASCO 2021), the MTD was 60 mg q3w and the recommended dose for expansion (RDE) was selected as 45 mg q3w. Methods: In Part B (dose expansion), patients received BI 907828 45 mg q3w. The primary endpoint was PFS. Secondary endpoints/objectives included objective response rate, overall survival, the number of patients with grade ≥3 treatment-related AEs, and PK parameters. Here, we report overall safety data and efficacy data in the subgroup of patients with advanced LPS. Results: As of January 10, 2022, 90 patients had been enrolled; 49 (54.4%) were male, 55 (61.1%)/34 (37.8%) were ECOG PS 0/1, the median number of prior systemic therapies was 2 (range, 0–11), 44 had advanced LPS (28 DDLPS, 16 well-differentiated LPS [WDLPS]). At data cut-off, 31/90 patients (34.4%) had received treatment for ≥6 months. In the 41 evaluable patients with advanced LPS, best response of PR or SD was observed in 24/27 patients with DDLPS (88.9%) and 13/14 patients with WDLPS (92.9%). Two DDLPS and 4 WDLPS patients achieved a PR; all had MDM2-amplified disease. In Part A, 5/11 DDLPS patients and 4/8 WDLPS patients have achieved PFS ≥10.5 months. In the 42 patients who received the RDE of 45 mg q3w, 18 patients (42.9%) had grade ≥3 AEs; the most common grade ≥3 AEs were neutropenia (23.8%), thrombocytopenia (21.4%), and anemia (11.9%). Seven patients (16.7%) had SAEs; the most common were thrombocytopenia (4.8%) and pyrexia (4.8%). PK analysis showed that mean plasma exposures (Cmax and AUC0-inf) increased with dose and showed no significant deviation from linearity in the dose range 10–60 mg. A correlation was observed between exposure and GDF-15 levels in plasma, as a target engagement marker. Conclusions: BI 907828 showed a manageable safety profile, high plasma exposure, target engagement and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. The Part B dose expansion is ongoing. Clinical trial information: NCT03449381.

Alpha-band EEG suppression as a neural marker of sustained attentional engagement to conditioned threat stimuli.

Attention helps us to be aware of the external world, and this may be especially important when a threat stimulus predicts an aversive outcome. Electroencephalogram (EEG) alpha-band suppression has long been considered as a neural signature of attentional engagement. The present study was designed to test whether attentional engagement, as indexed by alpha-band suppression, is increased in a sustained manner following a conditioned stimulus (CS) that is paired with an aversive (CS+) vs neutral (CS-) outcome. We tested 70 healthy young adults in aversive conditioning and extinction paradigms. One of three colored circles served as the CS+, which was paired in 50% of the trials with a noise burst (unconditioned stimulus, US). The other colored circles (CS-) were never paired with the US. For conditioning, we found greater alpha-band suppression for the CS+ compared to the CS-; this suppression was sustained through the time of the predicted US. This effect was significantly reduced for extinction. These results indicate that conditioned threat stimuli trigger an increase in attentional engagement as subjects monitor the environment for the predicted aversive stimulus. Moreover, this alpha-band suppression effect may be valuable for future studies examining normal or pathological increases in attentional monitoring following threat stimuli.

Emotional engagement in Thai and Japanese insurance advertising: corpus-based keyword analysis

Advertisements demonstrate patterns of communication that are imagined to be acceptable to the communities at which they are aimed, serving as cultural artefacts that provide insights into shared cultural interpretations and social interactions. Drawing on techniques from corpus linguistics, text linguistics and the Appraisal framework, we conducted an analysis of salient keywords in a collection of Thai and Japanese tv commercials (tvcs) for insurance products in order to identify statistically significant keywords and examine emotional engagement. We reveal how specific keywords and communicative strategies used in the persuasive discourse of the insurance products reflect Thai and Japanese socio-cultural preferences and values. We found that while Thai tvcs demonstrate a higher audience engagement through the use of metadiscourse markers such as engagement markers and emphatics under the theme of moral and family values, Japanese tvcs highlight information-dense content-words, including the extensive use of statistics involving themes of security, health and value propositions.

Dialogic interaction with diversified audiences in Twitter for Research Dissemination Purposes

International research groups are expected to ensure global dissemination and visibility of their knowledge production, for which Twitter is effectively employed to reach diversified audiences. This paper analyses the dialogic dimension of tweets published in accounts of Horizon2020 research projects, where group’s productivity and work are promoted, and multiple readers addressed. Our study focuses on the use, in these Twitter accounts, of interactional pragmatic strategies, their verbal realisation through engagement markers, as well as on medium affordances and non-verbal markers. A sample of 1.454 tweets from 10 accounts of the EUROPROtweets corpus were coded and analysed through NVivo. The data-driven pragmatic analysis triggered the identification of 8 interactional strategies. We then quantitatively analysed the use of engagement makers and qualitatively studied the characteristic non-verbal markers with a dialogic function within each of these. Our findings will help understand the complexities of current digital academic professional practices, especially as regards the dynamics of dialogic interaction in social media.

Incarceration exposure and prescription opioid use during pregnancy

BackgroundPrior research demonstrates a high prevalence of substance use, including opioid use, among those who have had personal or vicarious contact with the correctional system. Relatedly, alongside patterns of rising opioid use in general, opioid use during pregnancy is becoming a growing public health concern. Still, risk factors for prescription opioid use during pregnancy remain understudied. This study is the first to assess the connection between a women’s personal or vicarious exposure to incarceration in the 12 months prior to birth and patterns of prenatal opioid use. MethodsData are from the Pregnancy Risk Assessment Monitoring System (PRAMS) in 2019 (N = 17,551 mothers). Logistic and multinomial logistic regression are used to assess the association between incarceration exposure and patterns of opioid use during pregnancy. ResultsIncarceration-exposed women were more likely to use all eight types of prescription opioids assessed in this study (Hydrocodone, Codeine, Oxycodone, Tramadol, Hydromorphone/Meperidine, Oxymorphone, Morphine, and Fentanyl). After adjustment for control variables, incarceration-exposed women were significantly more likely to report any prescription opioid use during pregnancy (OR = 1.745, 95% CI = 1.194, 2.554). Furthermore, relative to no opioid use, incarceration exposure was also associated with illicit prescription opioid use (RRR = 2.979, 1.533, 5.791). ConclusionsIncarceration exposure in the year prior to birth is associated with higher odds of prescription opioid use. These findings add to the burgeoning literature that details a women’s exposure to incarceration is a risk marker for substance use and engagement in health risk behaviors that can jeopardize maternal and infant wellbeing.

Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS

Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across 6 species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varied dramatically across different brain regions in mice, cynomolgus macaques, and humans. PrP expression did not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP was lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55%, and D178N just 31%, of the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA was reflected in brain parenchyma PrP and, in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.

Interactional Linguistic Resources in Concession Speeches: An appraisal of Selected Political Leaders in Ghana and the United States of America

The purpose of the study was to examine the interactional linguistic resources in concession speeches of Selected Political Leaders in Ghana and the United States of America. The past three decades have witnessed an increasing scholarly interest in political discourse. Despite this, concession speeches have received limited scholarly attention. This study, therefore, comparatively analyzed the concession speeches delivered by John Dramani Mahama and Nana Addo Danquah Akuffo-Addo of Ghana and Hillary Clinton and Al Gore of the United States of America. Speech Act and Metadiscourse Interactionist Theories were used to examine the interpersonal linguistic resources found in the speeches. The speeches, were analyzed qualitatively. The study concluded that speakers of CSs in the two different cultural contexts use similar statements, as has already been discussed earlier in this study. For instance, the four losing candidates used almost the same interpersonal linguistic resources (hedges, boosters, self-mention, attitude markers, and engagement markers) to establish a bond between them and their interlocutors and supporters. It is recommended that, concession speeches (CSs) to be studied from other theoretical perspectives, this will allow for a detailed analysis of a wider range of linguistic resources such as noun phrases, verb phrases, and the use of adjuncts, beyond the SAs in CSs in order not to treat them as mere rhetoric in politics.

Linguistic Strategies Analysis on the Official Website of Indonesia Tourism

This study deals with Linguistic Strategy in the text on the Official Website of Indonesia Tourism (www.indonesia.travel). It is aimed to investigated the type of linguistic strategy based on functions and language features and the realization of lainguistic strategy on the Official Website of Indonesia Tourism. The study is applied descriptive qualitative. The data of this study is the text contained on the Official Website of Indonesia Tourism. There are 100 data that were analyzed based on Miles and Huberman, including condensation data, display data and conclusion drawing. This study find out that there were two types of linguistic strategy used in the official website of Indonesian tourism, namely: Informative Strategy and Persuasive Strategy. It also found that linguistic strategy was realized in Indonesian tourism websites through five Interactional Metadiscourse markers based on the theory of Hyland and Tse (2004) namely Hedges, Booster, Attitude Markers, Engagement Markers and Self-mentions.

Engagement Markers in Discussion Section of Research Articles Written by English Education Students and Articles Published in Reputable English Journal

Engagement Markers in Discussion Section of Research Articles Written by English Education Students and Articles Published in Reputable English Journal

An Analysis of Interactional Metadiscourse Markers in Political Science Research Articles

The study examined the interactional metadiscourse markers used in higher and lower tiered political science research articles. The specific aspects studied were: (1) the frequencies of five categories of interactional markers; and (2) the distribution of interactional markers by rhetorical sections. The descriptive study which involved the analysis of political science research articles published in 40 SCOPUS-indexed journals (20 Quartile 1; 20 Quartiles 3 and 4) conducted using Hyland’s (2005) interpersonal metadiscourse model identified 10,903 markers. Both Q1 and Q3-Q4 political science articles have boosters and hedges as the most frequently used markers, and engagement markers as the least used marker. There are significant differences between the higher and lower tiered political science research articles in the frequencies of interactional metadiscourse markers found in rhetorical sections. The method section has the most self-mentions, particularly in articles published in Q1 journals. Writers of articles published in Q1 journals prioritise boosters, indicating confidence in emphasising certainty, but writers of articles published in Q3-Q4 journals prioritise hedges over boosters. The Q1 articles have more attitude markers in the introduction and results-discussion-conclusion sections but less in the abstract and method sections, but writers of Q3-Q4 articles use attitude markers in similar frequencies across sections. The findings suggest that the nature of reader engagement varies with rhetorical sections in research articles.

Do cognitive impairments limit treatment gains in a standalone digital intervention for psychosis? A test of the digital divide

Digital mental health interventions, such as those provided by smartphone applications (apps), show promise as cost-effective approaches to increasing access to evidence-based psychosocial interventions for psychosis. Although it is well known that limited financial resources can reduce the benefits of digital approaches to mental healthcare, the extent to which cognitive functioning in this population could impact capacity to engage in and benefit from these interventions is less studied. In the current study we examined the extent to which cognitive functioning (premorbid cognitive abilities and social cognition) were related to treatment engagement and outcome in a standalone digital intervention for social functioning. Premorbid cognitive abilities generally showed no association with aggregated treatment engagement markers, including proportion of notifications responded to and degree of interest in working on app content, though there was a small positive association with improvements in social functioning. Social cognition, as measured using facial affect recognition ability, was unrelated to treatment engagement or outcome. These preliminary findings suggest that cognitive functioning is generally not associated with engagement or outcomes in a standalone digital intervention designed for and with people with schizophrenia spectrum disorders.

“Don’t Shop Here”: A Metadiscourse Analysis of Customer Reviews on Social Media

“Don’t Shop Here” is the title of a Facebook group that posts authentic customer reviews, written by Egyptians, on different products and services. Since these posts are a form of communication that takes place via electronic devices on the internet, it is considered a Computer-Mediated Discourse (CMD), also known as Computer-Mediated Communication (CMC). From the group title, the consumers’ posts that are published in the group are mostly negative, with a live interaction and comments by the group members, who sometimes include product/service providers among them. This study focuses on consumers’ interpersonal behavior that reveals their attitudes and evaluations. This is believed to be achieved by applying Hyland’s (2005) Metadiscourse Model. The model comprises several analytical tools that include engagement markers, hedges, boosters, attitude markers and self-mention that assist in describing the different relationships between customers and their audience, on the one hand, and customers and product/service providers, on the other hand.

The Use of Metadiscourse by Saudi and British Authors: A Focus on Applied Linguistics Discipline

This study investigated the use of metadiscourse tools by Saudi and British authors in Applied Linguistics discipline. In particular, the study tried to identify the kinds of metadiscourse markers used by Saudi and English authors in ALRAs and to determine the most and least frequent metadiscourse makers. In order to achieve these goals, (10) ALRAs written by Saudi authors and (10) ALRAs written by British authors served as the corpus of the study. The research articles were selected from well-known journals and published between 2010 – 2018. Hyland's (2005) model was used to find out the distribution of metadiscourse markers in each type of corpora. The findings showed interactive metadiscourse markers are used more than the interactional metadiscourse markers. Compared with the British authors, the Saudi authors were found to use metadiscourse markers more than the British authors. The Saudi authors employed all metadiscourse sub-categories more frequently than the British authors except frame markers, evidentials, endophoric markers, and self-mentions. In addition, it was found that transitions were the highly frequent metadiscourse markers in the whole corpora, followed by hedges, evidentials, boosters, and attitude markers, respectively. On the other hand, engagement markers were the least frequent metadiscourse markers in the whole corpora. 

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials.

The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.

The metadiscourse of Arabic academic abstracts: A corpus-based study

Research on metadiscourse and rhetorical features in modern Arabic academic writing is scarce both in quantity and in scope. Abstracts, in particular, are a severely understudied academic register. This study aims to fill a gap in the study of academic abstracts in Arabic by providing a more comprehensive analysis of metadiscourse in Arabic academic abstracts. The data for the study includes a corpus of 400 Arabic abstracts, which have been labeled according to two variables: (a) abstract type (journal or dissertation); and (b) author gender (male, female, mixed gender). The analysis follows the theoretical framework proposed by Hyland (2019), as the data has been annotated for both textual metadiscourse (transition markers, frame markers, evidentials, endophorics and code glosses) and interpersonal metadiscourse (hedges, boosters, attitude markers, engagement markers and self-mentions). Results show that Arabic academic abstracts are rich in both types of metadiscourse features. Transition and frame markers have the highest frequency in the textual domain, while boosters and self-mentions are highly frequent in the interpersonal domain. Endophoric markers and hedges are the least used types of metadiscourse in the data, but engagement markers are surprisingly more frequent than previously thought.

A Corpus Analysis of Engagement Markers in Facebook Status Updates: Exploring Age and Gender Effects

A Corpus Analysis of Engagement Markers in Facebook Status Updates: Exploring Age and Gender Effects

Engagement Markers in L1 and L2 English Academic Writing: The Case of Master’s and Doctorate Theses

Engagement markers are linguistic devices through which academic writers pull their readers into their texts and negotiate with them. This particular form of negotiation is crucial for the acceptance of new academic knowledge claimed by academic writers in addition to meeting the expectations of readers who are highly proficient scholars, specifically in postgraduate genres. A great deal of research has concentrated on the use of engagement markers in research articles. Hence, this study presents a comparative analysis of engagement markers in master’s and doctorate theses written by native academic writers of English and Turkish academic writers of English. The corpus is constructed for the investigation includes 1.148.992 words of master’s and doctorate theses written between 2010 and 2019 in English language-related fields. The concordance software, AntConc version 3.5.8, was utilized to calculate the frequency counts of engagement markers. We ran Log-likelihood statistics to determine whether there was a statistical difference among four corpora regarding engagement marker usage. In addition to cross-cultural variations in the two academic communities, we observed identical strategies in master’s and doctorate theses by both groups of academic writers.

Stance and engagement in selected Nigerian Supreme Court judgments

AbstractThe study investigates stance and engagement strategies of Nigerian Supreme Court judges in constructing arguments in their opinions. Fifty purposively selected judicial opinions were quantitatively and qualitatively analysed using Hyland’s stance and engagement model. The findings reveal that Nigerian Supreme Court judges used more stance than engagement features. Among the stance features found, the judges used more self-mention devices to establish authorial presence and distinguish their views from others. Prevalent among engagement markers, on the other hand, are directives, informed by the normative nature of the text and the judges’ keenness to owning such prescribed norms.

EEG as a Functional Marker of Nicotine Activity: Evidence From a Pilot Study of Adults With Late-Life Depression.

Late-life depression (LLD) is a debilitating condition that is associated with poor response to antidepressant medications and deficits in cognitive performance. Nicotinic cholinergic stimulation has emerged as a potentially effective candidate to improve cognitive performance in patients with cognitive impairment. Previous studies of nicotinic stimulation in animal models and human populations with cognitive impairment led to examining potential cognitive and mood effects of nicotinic stimulation in older adults with LLD. We report results from a pilot study of transdermal nicotine in LLD testing whether nicotine treatment would enhance cognitive performance and mood. The study used electroencephalography (EEG) recordings as a tool to test for potential mechanisms underlying the effect of nicotine. Eight non-smoking participants with LLD completed EEG recordings at baseline and after 12 weeks of transdermal nicotine treatment (NCT02816138). Nicotine augmentation treatment was associated with improved performance on an auditory oddball task. Analysis of event-related oscillations showed that nicotine treatment was associated with reduced beta desynchronization at week 12 for both standard and target trials. The change in beta power on standard trials was also correlated with improvement in mood symptoms. This pilot study provides preliminary evidence for the impact of nicotine in modulating cortical activity and improving mood in depressed older adults and shows the utility of using EEG as a marker of functional engagement in nicotinic interventions in clinical geriatric patients.