Syntactic adaptation leads to updated knowledge for local structural frequencies.

Syntactic adaptation has been shown to occur for various temporarily ambiguous structures, wherein an initially unexpected resolution becomes easier to process after repeated exposure. More controversial and less replicated is the claim that this adaptation towards a locally frequent structure occurs due to a strategic shifting of expectations to match short-term statistical regularities such that readers adapt away from the a priori more frequent structure. Experiment 1 replicates the initial adaptation towards a coordination garden path structure using self-paced reading; however, this paradigm has been criticised for its low reliability for detecting such small effects. To this end, Experiments 2 and 3 use a combination of self-paced reading and sentence completion tasks to replicate initial adaptation towards both coordination and reduced relative garden path structures and show evidence for a preference for these structures over their a priori more frequent alternatives. Together, these data reveal that participants may be tracking local structural statistics in real time; however, they may not be able to rapidly use that information to update processing behaviours.

Improving Access to Diagnostic Evaluations for Developmental Disabilities Through an Initial Assessment Model.

OBJECTIVE: This study aimed to evaluate a novel model of care to improve access to diagnostic evaluations for autism spectrum disorder and/or developmental delays for school-age children. METHODS: An "initial assessment" (IA) model for children aged 7 to 9 years was implemented at a large regional pediatric hospital. Referral patterns and the number of patients evaluated with the IA model were obtained through the electronic health record (EHR). Referral patterns from the EHR were checked against clinician surveys. RESULTS: Total IA volume had a strong negative association with school-age WL volume ( r (22) = -0.92, p < 0.001), indicating that as IA volume increased, the WL volume declined. Evaluation of referral patterns after IAs revealed that approximately 1 in 3 children seen for IA did not require further evaluation and could be immediately removed from the WL. CONCLUSION: Results indicate that implementation of a novel IA model was strongly associated with a decrease in WL volume for neurodevelopmental evaluations of school-age children. These findings support a "right-fit" approach to optimize clinical resources and improve access to neurodevelopmental evaluations.

Technology-Based Approaches for Supporting Perinatal Mental Health.

PURPOSE OF REVIEW: This review explores advances in the utilization of technology to address perinatal mood and anxiety disorders (PMADs). Specifically, we sought to assess the range of technologies available, their application to PMADs, and evidence supporting use. RECENT FINDINGS: We identified a variety of technologies with promising capacity for direct intervention, prevention, and augmentation of clinical care for PMADs. These included wearable technology, electronic consultation, virtual and augmented reality, internet-based cognitive behavioral therapy, and predictive analytics using machine learning. Available evidence for these technologies in PMADs was almost uniformly positive. However, evidence for use in PMADs was limited compared to that in general mental health populations. Proper attention to PMADs has been severely limited by issues of accessibility, affordability, and patient acceptance. Increased use of technology has the potential to address all three of these barriers by facilitating modes of communication, data collection, and patient experience.

Adaptation of infant mental health services to preterm infants and their families receiving neonatal intensive care unit services during the COVID-19 pandemic.

Multiple changes and stressors at the family, hospital, and societal levels have resulted from the COVID-19 pandemic that impact the early social environment of infants in Neonatal Intensive Care Unit (NICU) settings. This manuscript reviews these pandemic-related adversities, including hospital-wide visitor restrictions, mask requirements that interfere with caregiver facial expressions, parental anxiety about virus transmission, and reduced support services. We will further describe adaptations to mental health service delivery and approaches to care in the NICU to mitigate increased risk associated with pandemic-related adversities. Adaptations include integration of technology, staff education and support, and delivery of activity kits to encourage parent-infant bonding. Data was collected as part of routine program evaluation of infant mental health services from one 50-bed NICU setting and describes family concerns, barriers to visitation, and utilization of mental health services during the pandemic. Concerns related to COVID-19 rarely emerged as the primary presenting issue by the families referred for infant mental health services from April through December of 2020. However, a number of families indicated that infection concerns and visitation restrictions posed significant challenges to their parenting and/or coping. There were significant discrepancies noted between the visitation patterns of families with public and private insurance. Several adaptations were developed in response to the multiple challenges and threats to infant mental health present during the COVID-19 pandemic.

Múltiples factores de estrés a nivel de la familia, el hospital y la sociedad han resultado de la pandemia del COVID-19, los cuales han tenido un impacto en el temprano ambiente social de los infantes en el ambiente de la Unidad de Cuidados Intensivos Neonatales (NICU). Este artículo revisa estas situaciones adversas relacionadas con la pandemia, incluyendo las restricciones generales de visita al hospital, el requisito de llevar máscara que interfiere con las expresiones faciales de quien presta el cuidado, la ansiedad de los padres acerca de la transmisión del virus y los reducidos servicios de apoyo. Describimos además adaptaciones al ofrecimiento de servicios de salud mental en NICU para mitigar el aumento del riesgo asociado con las situaciones adversas relacionadas con la pandemia. Estas adaptaciones incluyen la integración de tecnología, la educación y el apoyo del personal, así como el ofrecimiento de material para actividades que promueven la unión afectiva entre progenitor e infante. Se recogió información como parte de la evaluación rutinaria del programa sobre los servicios sicosociales en el caso de una unidad NICU de 50 camas y se describen las preocupaciones de la familia, los obstáculos a la visita, así como la utilización de los servicios de salud mental infantil durante la pandemia. El COVID-19 raramente surgió como el principal asunto que enfrentaban las familias que fueron referidas para intervención de abril a diciembre de 2020. Sin embargo, algunas familias indicaron que las preocupaciones de adquirir una infección y las restricciones de visita presentaron retos significativos a la crianza y/o a la manera de arreglárselas. Se notaron discrepancias significativas entre los patrones de visita de familias con seguro público o con seguro privado. Como respuestas a estas amenazas a la salud mental infantil presentes durante la pandemia del COVID-19, se desarrollaron varias adaptaciones.

Des facteurs de stress multiples aux niveaux de la famille, de l'hôpital et de la société ont résulté de la pandémie du COVID-19 qui impacte l'environnement social précoce des nourrissons dans les Unités Néonatales de Soins Intensifs (UNSI). Cet article passe en revue ces adversités liées à la pandémie, y compris les restrictions pour les visiteurs dans les hôpitaux, les obligations de porter le masque qui interfèrent avec les expressions faciales de la personne prenant soin du bébé, l'anxiété parentale à propos de la transmission du virus et des services de soutien réduits. Nous décrivons des adaptations à la prestation de service de santé mentale dans l'UNSI afin de mitiger le risque accru associé aux adversités liées à la pandémie. Des adaptations ont inclus l'intégration de la technologie, la formation et le soutien aux employés, la livraison de kits d'activités afin d'encourager le lien parent-bébé. Des données ont été recueillies comme faisant partie de l'évaluation de routine de services psychosociaux dans le contexte d'une INSI de 50 lits et décrivent les inquiétudes familiales, les barrières aux visites, l'utilisation de services de santé mentale du nourrisson durant la pandémie. Le COVID-19 a rarement émergé comme étant le problème principal présenté par les familles ayant reçu une intervention d'avril à décembre 2020. Cependant certaines familles ont indiqué que les inquiétudes touchant à l'infection et les restrictions des visites ont posé des défis importants à leur parentage et/ou à leur adaptation. Des différences importantes ont été notées entre les patterns de visites des familles ayant une assurance publique et une assurance privée. Plusieurs adaptations ont été développées pour faire face aux dangers pour la santé mentale infantile présents durant la pandémie de COVID-19.

Misretrieval but not misrepresentation: A feature misbinding account of post-interpretive effects in number attraction.

Attraction effects in comprehension have reliably shown a grammaticality asymmetry in which mismatching plural attractors confer facilitatory interference for ungrammatical verbs, but no processing cost for grammatical verbs. While this has favoured cue-based retrieval accounts of attraction phenomena in comprehension, Patson and Husband offered offline evidence suggesting that comprehenders systematically misrepresent number information in attraction phrases, leaving open the possibility for faulty noun phrase (NP) representations later in processing. The current study employs two self-paced reading discourse experiments to test for number attraction misrepresentations in real time. Specifically, the attraction phrases occurred as embedded direct object phrases, allowing for a direct test of the role of attractor noun number in head noun number misrepresentation (i.e., no number cue from verb). Although no online evidence for misrepresentation was found, a third single-sentence rapid serial visual presentation experiment showed error rates to offline probes corroborating the post-interpretive findings from Patson and Husband, suggesting that a search in memory for associative features may not employ the same processes as the formation of dependencies in discourse comprehension. The findings are discussed in the framework of feature misbinding in memory in line with recent post-interpretive accounts of offline comprehension errors.

Adaptive Behavior Profiles of Intellectually Gifted Children with Autism Spectrum Disorder.

OBJECTIVE: The purpose of this study is to identify whether the well-described pattern of declining adaptive functioning across age among children with autism spectrum disorder (ASD) also exists among intellectually gifted children with ASD because their cognitive abilities might serve as a protective factor. METHODS: Data from the Simons Simplex Collection were used to identify 51 participants with full-scale intelligence (IQ) scores of 130 or above with this group labeled as the intellectually gifted range (IGR). Two comparison samples of children with IQs in the intellectual disability range (IDR; < 70 Standard Score [SS]) and average range (AR; 85-115 SS) were created based on matching of age (±2 years), maternal education level, and sex. RESULTS: Multivariate analysis of variance indicated a main overall effect for the IQ group on a measure of adaptive skills (Λ = 0.61, F(6, 296), p < 0.001). Post hoc comparisons revealed that the IDR group scored lower on all subscales than the AR and IGR groups, but the scores between the latter groups did not differ from one another in socialization and daily living skills (DLS) domains. Age was negatively correlated with adaptive communication scores in all groups but only associated with socialization and DLS domain scores in the IGR group (r = -0.51 and -0.48, respectively). CONCLUSION: The findings suggest that intellectual giftedness does not serve as a protective factor against age-related declines in adaptive functioning among individuals with ASD.

Primary contributors to gastrostomy tube placement in infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: To identify factors associated with gastrostomy tube (GT) placement in infants with congenital diaphragmatic hernia (CDH). METHODS: Retrospective cohort study of 114 surviving infants with CDH at a single tertiary care neonatal intensive care unit from 2010-2019. Prenatal, perinatal and postnatal characteristics were compared between patients who were discharged home with and without a GT. Prenatal imaging was available for 50.9% of the cohort. Logistic regression was used to assess the association between GT placement and pertinent clinical factors. ROC curves were generated, and Youden's J statistic was used to determine optimal predictive cutoffs for continuous variables. Elastic net regularized regression was used to identify variables associated with GT placement in multivariable analysis. RESULTS: GT was placed in 43.9% of surviving infants with CDH. Prenatal variables predictive of GT placement were percent predicted lung volume (PPLV) <21%, total lung volume (TLV) <30 ml, lung-head ratio (LHR) <1.2 or observed to expected LHR (O/E LHR) <55%. Infants who required a GT were diagnosed earlier prenatally (23.6 ± 3.4 vs. 26.4 ± 5.6 weeks). Patients whose stomach was above the diaphragm on prenatal ultrasound (up) had a higher odds of GT placement compared to those with stomachs below the diaphragm (down) position by a factor of 2.9 (95% CI: 1.25, 7.1); p = 0.0154. Postnatally, infants with GT had lower Apgar scores at 1 and 5 min, longer lengths of stay and higher proportion of flap closures. Infants with a type C or D defect and extracorporeal membrane oxygenation (ECMO) were associated with increased odds of needing a GT. Postnatal association included being NPO for >12 days, need for transpyloric (TP) feeds for >10 days, >14 days to transition to a 30 min bolus feed, presence of gastro-esophageal reflux (GER), chronic lung disease and pulmonary hypertension. In multivariable analysis, duration of NPO, time to TP feeds, transition to 30 min bolus feeds remained significantly associated with GT placement after adjusting for severity of pulmonary hypertension (PH), GER diagnosis and sildenafil treatment. CONCLUSION: Identification of risk factors associated with need for long-term feeding access may improve timing of GT placement and prevent prolonged hospitalization related to feeding issues. LEVEL OF EVIDENCE RATING: Level II (Retrospective Study).

Autism and Access to Care During the COVID-19 Crisis.

CASE: Brian is a 6-year-old boy who was diagnosed with autism spectrum disorder (ASD) and global developmental delay at age 2. He has no other health conditions of note. Brian lives with his parents and an older brother, who also has ASD, in a rural area 2 hours from the center where he was diagnosed. Brian has a history of intermittent self-injurious behaviors (head-banging, throwing himself onto the floor, etc.) that regularly result in bruising, intense and lengthy tantrums, and aggression toward family and teachers. Brian will occasionally indicate items that he wants, but otherwise has no functional communication skills. Over the past 18 months, Brian's challenging behaviors have waxed and waned. The regional special education program is not equipped to safely manage his behaviors, and there are no in-home or center-based agencies that provide applied behavior analysis (ABA) available. Brian's developmental pediatrician initiated guanfacine (eventually adding a small dose of aripiprazole) and referred the family to psychology for weekly telehealth behavioral parent training to address behavioral concerns using the Research Units in Behavioral Intervention curriculum.1Brian's behavioral problems decreased during the initial weeks of the COVID-19 crisis, when he no longer had to leave home or attend special education. However, as summer continued, his behaviors worsened substantially (regular bruising and tissue damage, numerous after-hours consultations with his psychologist and developmental pediatrician, and one trip to the emergency department). The intensity of Brian's behaviors (maintained primarily by access to tangible items and escape from demands) made progress with behavioral supports slow and discouraging for his parents. Other psychosocial stressors coalesced for the family as well, including employment loss, limited social support because of social distancing requirements, and illness of one of his parents. The developmental pediatrician continued to modify the medication regimen over the summer, transitioning Brian from guanfacine to clonidine and increasing his aripiprazole incrementally (with clear increased benefit); hydroxyzine was also used as needed during the episodes of highest intensity.Despite the availability of best-practice guidelines for children with Brian's presenting concerns,2 a confluence of barriers (geographic, economic, ABA work force, global pandemic, etc.) present serious questions for his family and care team related to the next steps in Brian's care. Should he attend in-person school in the fall, knowing that the available program may have limited educational benefit and increase his risk of COVID-19 exposure (not to mention self-injury)? Would the potential benefits of cross-country travel to an intensive behavioral treatment program outweigh the associated psychosocial and economic stressors? How else can the virtual care team support this family? REFERENCES: 1. Bearss K, Johnson C, Smith T, et al. Effect of parent training vs parent education on behavioral problems in children with autism spectrum disorder: a randomized clinical trial. JAMA. 2015;313: 1524-1533.2. Hyman SL, Levy SE, Myers SM, et al. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics. 2020;145:e20193447.

Evaluating Two Common Strategies for Research Participant Recruitment Into Autism Studies: Observational Study.

BACKGROUND: Ongoing research is necessary to better understand the causes of autism spectrum disorder (ASD), the developmental outcomes for individuals diagnosed with ASD, and the efficacy of the interventions. However, it is often difficult to recruit sufficient numbers of participants for studies, and despite the prevalence of ASD (currently estimated to affect 1 in 54 children), little research has focused on how to efficiently recruit participants with ASD. OBJECTIVE: The aim of this study was to determine the efficacy of two different paid advertisements-social media and radio advertising-in recruiting participants for a study enrolling people with ASD and their family members by examining the number of participants enrolled, the cost per participant, and the geographic reach of each type of advertising. METHODS: We examined participant enrollment in a study following nonoverlapping paid advertisements on a popular FM radio station (aired in three cities across two states) and Facebook (six advertisements that ran in five cities across two states). The total paid investment in the radio campaign was $12,030 and that in the Facebook campaign was $2950. Following the advertising campaigns, 1391 participants in the study who were affiliated with the Houston, Texas, site received email invitations to participate in a brief survey about the ways in which they learned about the study (eg, social media, medical provider, website) and which of these were most influential in their decisions to participate; 374 (26.8%) of the participants completed this survey. RESULTS: Social media advertising outperformed radio in all three parameters examined by enrolling more participants (338 vs 149), with a lower average cost per participant ($8.73 vs $80.74) and a wider geographic reach, based on a comparison of the number of zip codes within and outside of Texas for questionnaire respondents who rated social media as the most influential method of contact (n=367, χ21=5.85, P=.02). Of the 374 survey participants, 139 (37.2%) reported that they had seen the study on social media prior to enrollment, while only 9 (2.4%) said they heard about it via radio. CONCLUSIONS: Our findings suggest that advertising on social media can efficiently reach a large pool of potential participants with ASD, increasing the likelihood of meeting study enrollment goals. Researchers should consider allocating at least some portion of recruitment dollars to social media platforms as a means of quickly and inexpensively reaching out to their target populations, including for studies with in-person procedures.

Convergent probabilistic cues do not trigger syntactic adaptation: Evidence from self-paced reading.

Previous work has ostensibly shown that readers rapidly adapt to less predictable ambiguity resolutions after repeated exposure to unbalanced statistical input (e.g., a high number of reduced relative-clause garden-path sentences), and that these readers grow to disfavor the a priori more frequent (e.g. main verb) resolution after exposure (Fine, Jaeger, Farmer, & Qian, 2013). However, recent work has failed to replicate effects indicating a penalty for the a priori preferred, more frequent continuation, despite finding a speedup in syntactic repair times after initial exposure to the dispreferred, infrequent structure (Harrington Stack, James, & Watson, 2018). The current study reports three self-paced reading experiments that test whether co-occurring cues (explicit comprehension questions, preceding semantic cues, and font color) help facilitate adaptation to reduced relative/main verb garden-path sentences. Results suggest that readers do not overcome preexisting expectation biases by rapidly adapting to statistically novel linguistic contexts even with convergent probabilistic cues. An emphasis is placed on the difference between syntactic satiation effects and expectation adaptation, the latter of which we argue can only be determined through a penalty for an a priori preferred resolution after repeated exposure to its a priori less-preferred counterpart. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib.

The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms that protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity.

Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy.

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.

Screening and Referral Practices for Autism Spectrum Disorder in Primary Pediatric Care.

OBJECTIVES: To examine screening practices for autism spectrum disorder (ASD), subsequent referrals, and diagnostic outcomes within a large network of primary pediatric care practices. METHODS: Rates of ASD screening with the Modified Checklist for Autism in Toddlers (M-CHAT) at 18- and 24-month well-child visits were examined among 290 primary care providers within 54 pediatric practices between June 2014 and June 2016. Demographic, referral, and diagnostic data were abstracted from the medical records for all children who failed the M-CHAT (ie, score of ≥3) at either or both visits. RESULTS: Rates of M-CHAT screening were 93% at 18 months and 82% at 24 months. Among 23 514 screens, scores of 648 (3%) were ≥3 (386 at 18 months, 262 at 24 months) among 530 unique children who failed 1 or both screenings. Among screen-failed cases, 18% received a diagnosis of ASD and 59% received ≥1 non-ASD neurodevelopmental disorder diagnosis within the follow-up period. Only 31% of children were referred to a specialist for additional evaluation. CONCLUSIONS: High rates of ASD-specific screening do not necessarily translate to increases in subsequent referrals for ASD evaluation or ASD diagnoses. Low rates of referrals and/or lack of follow-through on referrals appear to contribute to delays in children's receipt of ASD diagnoses. Additional education of primary care providers regarding the referral process after a failed ASD screening is warranted.

Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling.

PURPOSE: Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study, we evaluated abemaciclib, a small-molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. EXPERIMENTAL DESIGN: Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of ES as either a monotherapy or in combination with chemotherapy. RESULTS: Abemaciclib induced quiescence in ES cell lines via a G1 cell-cycle block, characterized by decreased proliferation and reduction of Ki-67 and FOXM1 expression and retinoblastoma protein (RB) phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single-agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. CONCLUSIONS: Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.

Exploring the contribution of motivation and experience in the postpubescent own-gender bias in face recognition.

The own-gender bias in face recognition has been hypothesized to be the result of extensive experience with own-gender faces, coupled with a motivation to process own-group faces more deeply than other-group faces. We test the effect of experience and motivation in four experiments employing standard old/new recognition paradigms. In Experiment 1, no own-gender recognition bias was observed following an attractiveness-rating encoding task regardless of school type (single- or mixed-sex). Experiment 2, which used a distinctiveness-rating encoding task, did find a significant own-gender bias for all groups of participants. Experiment 3 on adults found that the own-gender bias was not affected by self-reported contact with the other-gender, but the encoding task did moderate the size of the bias. Experiment 4 revealed that participants with an own-gender sexual orientation showed a stronger own-gender bias. These results indicate that motivational factors influence the own-gender bias whereas no evidence was found for perceptual experience. (PsycINFO Database Record

The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade.

Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity.

Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib.

Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.