Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.

In this work, we use a mathematical model of the property listing task dynamics and test its ability to predict processing time in semantic and lexical decision tasks. The study aims at exploring the temporal dynamics of semantic access in these tasks and showing that the mathematical model captures essential aspects of semantic access, beyond the original task for which it was developed. In two studies using the semantic and lexical decision tasks, we used the mathematical model’s coefficients to predict reaction times. Results showed that the model was able to predict processing time in both tasks, accounting for an independent portion of the total variance, relative to variance predicted by traditional psycholinguistic variables (i.e., frequency, familiarity, concreteness imageability). Overall, this study provides evidence of the mathematical model’s validity and generality, and offers insights regarding the characterization of concrete and abstract words.

Dementia is a syndrome characterized by cognitive and neuropsychiatric symptoms associated with progressive functional decline (FD). FD is a core diagnostic criterion for dementia, setting the threshold between its prodromal stages and the full-blown disease. The operationalization of FD continues to generate a great deal of controversy. For instance, the threshold of FD for the diagnosis of dementia varies across diagnostic criteria, supporting the need for standardization of this construct. Moreover, there is a need to reconsider how we are measuring FD to set boundaries between normal aging, mild cognitive impairment, and dementia. In this paper, we propose a multidimensional framework that addresses outstanding issues in the assessment of FD: i) What activities of daily living (ADLs) are necessary to sustain an independent living in aging? ii) How to assess FD in individuals with suspected neurocognitive disorders? iii) To whom is the assessment directed? and iv) How much does FD differentiate healthy aging from mild and major neurocognitive disorders? Importantly, the To Whom Question introduces a person-centered approach that regards patients and caregivers as active agents in the assessment process of FD. Thus, once impaired ADLs have been identified, patients can indicate how significant such impairments are for them in daily life. We envisage that this new framework will guide future strategies to enhance functional assessment and treatment of patients with dementia and their caregivers.

Abstract Multimodal integration is crucial for human interaction, in particular for social communication, which relies on integrating information from various sensory modalities. Recently a third visual pathway specialized in social perception was proposed, which includes the right superior temporal sulcus (STS) playing a key role in processing socially relevant cues and high-level social perception. Importantly, it has also recently been proposed that the left STS contributes to audiovisual integration of speech processing. In this article, we propose that brain areas along the right STS that support multimodal integration for social perception and cognition can be considered homologs to those in the left, language-dominant hemisphere, sustaining multimodal integration of speech and semantic concepts fundamental for social communication. Emphasizing the significance of the left STS in multimodal integration and associated processes such as multimodal attention to socially relevant stimuli, we underscore its potential relevance in comprehending neurodevelopmental conditions characterized by challenges in social communication such as autism spectrum disorder (ASD). Further research into this left lateral processing stream holds the promise of enhancing our understanding of social communication in both typical development and ASD, which may lead to more effective interventions that could improve the quality of life for individuals with atypical neurodevelopment.

Abstract Comprehensive next-generation sequencing (NGS) panels designed to identify the tumor mutational profile are becoming the standard care to prescribe target therapies in developed countries. In non-small cell lung cancer (NSCLC), this approach significantly impacts the patient´s clinical results, measured as progression-free survival and/or overall survival, compared to conventional chemotherapies. However, as Latin American patients tend to experience more significant health disparities because of structural, sociodemographic, and psychosocial factors, in this work, our purpose is to measure the disparities in the access to NSCLC´s target therapies, specifically in Chile. DNAs and RNAs from 1643 NSCLC samples from Chile, Brazil, and Peru were sequenced to assess the mutational status in fifty-two cancer genes. After an NGS quality control, variants were called and annotated using the Variant Effect Predictor, Annovar, COSMIC, and OncoKB, to categorize somatic mutations. The following analysis focused on today’s actionable genes in NSCLC, with FDA-approved target therapies (EGFR, KRAS, ALK, MET, ERBB2, BRAF, ROS1, and RET). In this analysis, 46.5% of tumors evidenced driver mutations (764/1643); interestingly, from this subset, 86.9% showed one driver variant, 11.2% two drivers, 1.4% three drivers, and 0.5% evidenced between 4-6 driver mutations. However, 19.4% (495/1643) evidenced actionable variants. The most mutated genes and the most common actionable variants were 15.3% EGFR (37% EGFR L858R), followed by 4.9% KRAS (100% KRAS G12C), 4.5% ALK (95.4% EML4-ALK fusion), 3% MET (100% MET exon 14 skipping), and 2.3% ERBB2. Finally, 1.5% BRAF, 1% ROS1 gene fusions and 0.9% RET gene fusions. Considering the target therapies approved by Chile´s Instituto de Salud Publica until October 2021, and if all these patients were diagnosed in Chile, only 64% would receive a targeted drug. EGFR is the gene with more target therapies validated in Chile, although drugs against exon twenty insertion have not been approved yet. Chile does not account for any targeted treatment for patients with alterations in KRAS, MET, RET and ERBB2; although the FDA approved a specific drug against KRAS G12C very recently (May 28, 2021), different is the case of MET because the first inhibitor, crizotinib, was FDA approved four years ago. Interestingly, in 2021, two inhibitors against the most common MET alteration were FDA approved, but none have been approved in Chile yet. In Chile, almost all target therapies have been validated against EGFR, ALK, and BRAF; however, patients with KRAS, MET, RET, and ERBB2 cannot access specific drugs, so in these cases, the recommended therapeutic option is chemotherapy. It is important to note that the target drugs approval only ensures the availability of the drug in Chile. Still, few of the target drugs are part of financed drugs by the Chilean health system, so the question is, how could we increase the national access to existing target therapies? Citation Format: Solange V. Rivas, Evelin González, Alejandro Blanco, Carolina Ibáñez, Alejandro Corvalán, Marcelo Garrido, Gareth Owen, Katherine Marcelain, Ricardo Armisén. Disparities in the access to non-small cell lung cancer´s target therapies in Chile [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C018.

Abstract This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Abstract Introduction The consumption of alcohol, tobacco, and cannabis is a public health problem that impacts the cognitive, social, and emotional development of adolescents. Prevention strategies such as the “Unplugged” program are effective in delaying the progression of daily smoking and episodes of drunkenness among adolescents. “Yo Se Lo Que Quiero” (YSLQQ) corresponds to the adaptation of this program to the Chilean context. This study assesses the acceptability and feasibility of implementing this program to the local reality. Material and methods This was a cluster-randomized controlled pilot study conducted on six public schools. All consented students attending 6th, 7th, and 8th grades (n = 1,180) participated in the study. The schools were randomly assigned to one of two conditions in a 1:1 ratio: (1) the “YSLQQ” intervention group (n = 526), and (2) the Control group (n = 654). The program consisted of a 12-hour class-based curriculum based on a comprehensive social-influence approach delivered by a trained facilitator. The acceptability and feasibility were assessed in the intervention group at the end of the intervention using questionnaires answered by students and facilitators. The quality and fidelity of the program were evaluated during the implementation using self-ported surveys answered by the facilitators and the assessment of video-recorded sessions rated by external observers. Finally, a pre-test and a post-test survey assessing past and current substance use and risk and protective factors were conducted before and immediately after the program’s implementation. Results A high proportion of students (49.6%) liked the sessions. 79.2% reported that the YSLQQ helped them learn about the dangers of substances, while 65.8% reported having more skills to avoid substance use in the future. Regarding students’ satisfaction with YSLQQ, 62.9% reported being happy or very happy with the program. Facilitators reported implementing the intervention according to the manual in 73.9% of sessions. Regarding substance use, students who participated in the intervention groups reported a significant reduction in drunkenness in the last year and last 30-day prevalence and also a significant reduction in a lifetime and 30-day prevalence of cannabis use when compared with those students in the control group. Conclusions Our results suggest that YSLQQ has adequate acceptability and feasibility to be implemented in the Chilean context, and there were promising results in reducing drunkenness and cannabis use. Future research should confirm these results in a larger RCT study. Trial registration The trial was registered in ClinicalTrials.gov, NCT04566627; registration date: 01/03/2019

Multiple studies have demonstrated that acute ethanol consumption alters brain function and cognition. Nevertheless, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity, and recently, the opening of hemichannels has been found to play a relevant role in this process. Hemichannels are plasma membrane channels composed of six connexins or seven pannexins, respectively, that oligomerize around a central pore. They serve as ionic and molecular exchange conduits between the cytoplasm and extracellular milieu, allowing the release of various paracrine substances, such as ATP, D-serine, and glutamate, and the entry of ions and other substances, such as Ca2+ and glucose. The persistent and exacerbated opening of hemichannels has been associated with the pathogenesis and progression of several brain diseases for at least three mechanisms. The uncontrolled activity of these channels could favor the collapse of ionic gradients and osmotic balance, the release of toxic levels of ATP or glutamate, cell swelling and plasma membrane breakdown and intracellular Ca2+ overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca2+ signaling and gliotransmitter release. Acute ethanol exposure triggered the rapid activation of connexin43 and pannexin1 hemichannels in astrocytes, as measured by time-lapse recordings of ethidium uptake. This heightened activity derived from a rapid rise in [Ca2+]i linked to extracellular Ca2+ influx and IP3-evoked Ca2+ release from intracellular Ca2+ stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca2+]i. The [Ca2+]i-dependent activation of hemichannels elicited by ethanol caused the increased release of ATP and glutamate in astroglial cultures and brain slices. Our findings offer fresh perspectives on the potential mechanisms behind acute alcohol-induced brain abnormalities and propose targeting connexin43 and pannexin1 hemichannels in astrocytes as a promising avenue to prevent deleterious consequences of alcohol consumption.