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Autistic youth often experience psychiatric complexity, with up to 70 % of youth experiencing at least one mental health issue, and as many as 41 % experiencing two or more issues simultaneously, or complex psychiatric comorbidity. Adapted cognitive behaviour therapy (CBT) for anxiety is effective in reducing anxiety symptoms in autistic youth who have multiple anxiety conditions, as well as other psychiatric conditions (e.g., attention deficit hyperactivity disorder; ADHD). However, few studies have examined the secondary impact of CBT for anxiety on depressive symptoms, despite the high prevalence of depression in autistic youth. Additionally, it is unknown how psychiatric complexity may impact, or moderate, autistic youth's response to treatment. Fifty-one autistic youth (8–13 years old) participated in an adapted CBT intervention for anxiety (Facing Your Fears). Participants were categorized into one of three groups of increasing psychiatric complexity (Anxiety only; Anxiety + ADHD; and Anxiety + other mental health conditions). Paired sample t-tests and linear mixed models highlighted that autistic youth generally benefitted from CBT for anxiety, as seen in reductions of anxiety and depressive symptoms. Caregivers of youth in all diagnostic groups reported a significant reduction in anxiety symptoms and depression at post-treatment; however, only youth in the Anxiety only group, or those with less psychiatric complexity, reported a reduction in anxiety. Autistic youth did not report any changes in depressive symptoms, regardless of psychiatric complexity. Further study is needed to determine if symptom reductions continue overtime, and whether participating in adapted CBT for anxiety is associated with reductions in other mental health symptoms. • Adapted cognitive-behavioural interventions, such as Facing Your Fears (FYF), are effective in reducing anxiety in autistic youth; however, it is unknown if these interventions impact depressive symptoms. • Here, we 1) investigated how participating in FYF impacts anxiety and depressive symptoms and 2) examined how the degree of psychiatric complexity may moderate this association in autistic youth (8-13 years of age; n=51). • According to caregivers, autistic youth generally benefited from participating in FYF, as seen by a reduction of anxiety and depressive symptoms, regardless of psychiatric complexity. • Only autistic youth with less psychiatric complexity (i.e., anxiety only) reported a reduction in anxiety from pre- to post-treatment, and autistic youth did not report any changes in depression, regardless of psychiatric complexity. • These findings highlight that transdiagnostic approaches may be especially beneficial in supporting the mental health needs of autistic youth. [ABSTRACT FROM AUTHOR]

We and others have shown that Chk-1/2 inhibition (Chk-i) in combination with ionizing radiation (IR) has significant preclinical and clinical antitumor effects in head and neck squamous cell carcinoma (HNSCC). However, biomarkers of resistance and maximizing response to combination Chk-i and IR have been elusive. Here, utilizing TCGA and clinical trial data as well as preclinical models of Chk-i resistance, we report tumor intrinsic immune signatures of Chk-1/2 activity and inhibitor sensitivity. Gene Ontology (GO) enrichment analysis of HNSCC samples with CHK1/2 gene amplification or overexpression was performed utilizing RNAseq data extracted from TCGA. Using human HNSCC cells, UM-SCC1, secondary Chk-i resistance was generated via serial Chk-i exposure, whereby tolerance of resistant SCC-1 (R-SCC1) cells exceeded the IC50 by 10-fold. Tumor cell-directed immune regulators were quantified by qPCR +/- Chk-i and/or IR. Multiplex gene profiling was performed on pre-treatment tumor samples from patients enrolled in a phase 1b clinical trial of a Chk-i and IR. TCGA analysis revealed CHK1/2 activity negatively correlates with innate immunity, inflammation and granulocyte chemotaxis, as these GO scores were significantly quelled in CHK1/2 amplified or overexpressed tumor samples, signifying a suppressive interplay between Chk-1/2 signals and anti-tumor immunity. qPCR revealed enhanced immune signatures related to recruitment of tumor associated macrophages (TAMs) in R-SCC1 as compared to SCC1, which was proportionally enhanced by Chk-i. The addition of IR differentially altered key facilitators of TAMs in SCC1 versus R-SCC1, such as increased CSF1 in R-SCC1 cells only, and decreased CXCL14 with a greater effect observed in SCC1. Further supporting a role of Chk-1/2 inhibitor sensitivity in immune suppression, baseline and Chk-i induced STAT6 expression, which may inhibit immune tolerogenic M2-macrophage polarization, was decreased in R-SCC1 as compared to SCC1. Baseline STAT1 gene expression was also elevated in SCC1 versus R-SCC1. Consistent with TCGA and preclinical data, clinical trial analyses support a link between tumor-directed immune signatures and Chk-i sensitivity, as tumors from HNSCC patients responsive to Chk-i were enriched in Th1 subsets and poorly responsive patient samples exhibited enhanced M2-macrophage activity. Our study reveals a link between CHK1/2 activity and immune surveillance, as well as identifies key mediators of immune activation and macrophage polarization specific to Chk-i resistance, altogether implicating a mechanism of immune suppression that impedes clinical response to Chk-i + IR. Future studies validating tumor-directed immune signatures as biomarkers of efficacy of Chk-1/2 inhibition and identifying targetable mediators to enhance responsiveness are warranted. [ABSTRACT FROM AUTHOR]

Prexasertib is a checkpoint kinase 1 (Chk-1) inhibitor that induces tumor cell apoptosis through bypassing DNA repair checkpoints. We and others have shown that prexasertib in combination with chemotherapy with or without radiation (RT) has significant antitumor effects in both in vitro and in vivo models of head and neck squamous cell carcinoma (HNSCC). Recently, we reported the results of a phase 1b trial assessing the safety and efficacy of prexasertib in combination with cetuximab-RT or cisplatin-RT (Yang et al. Radiotherapy and Oncology 2021). In this study, we report tumor and immune biomarker analyses from this trial. Gene expression profiling using multiplex analysis platform and panels was performed on archival tumor tissue obtained prior to administration of prexasertib in combination with RT and either cisplatin or cetuximab from 17/25 patients with locally advanced HNSCC enrolled in a Phase 1b study (NCT02555644). Differentially expressed genes were compared between patients with complete response (CR) and not complete response (NCR; includes partial response, progressive and stable disease), as defined by RECIST criteria. Immune gene signatures that correlated with prexasertib clinical response involved Th1 T cell and M1 macrophage phenotypes. While exhausted CD8+ T and Treg cell gene scores, as well as PD-L1 mRNA levels, were higher in tumors from CR patients, we found significantly higher immune tolerogenic M2 macrophage-associated gene expression and increased CSF1 tumor cell signaling in NCR patients. Gene expression of functional markers of T and NK cells, including IL-2, IFN-γ, granzyme and perforin, were similarly elevated in CR patients with correspondingly increased tumor mRNA levels of JAK/STAT signaling elements such as JAK2, STAT1/3, and IFNG. Conversely, Wnt/β-catenin pathway mediators CTNNB1 and AXIN2, as well as IL-6 mRNA levels, which may mediate immune exclusion, were upregulated in NCR patients. Consistent with our prior preclinical observations, Notch signaling activators JAG1/2, which are implicated in maintaining cancer stem cells, apoptosis inhibition and tumor growth, were found to be elevated in NCR patients. Gene expression analysis found that baseline immune and tumor gene signatures correlated with Chk-1 inhibitor sensitivity in patients receiving chemo-RT. Findings suggest that oncogenic pathway activity and intact immune surveillance may be important in response to combination of prexasertib with RT, and that baseline immunosuppressive tumor microenvironments may impede maximal Chk-1 inhibitor efficacy. Future studies aimed to validate tumor and immune signatures as biomarkers of efficacy of Chk-1 inhibition and to identify targetable mediators to enhance responsiveness are warranted. [ABSTRACT FROM AUTHOR]

Over 50 % of children and youth with cerebral palsy (CP) experience mental health challenges, with anxiety and depression most common. Youth with CP also experience several physiological symptoms such as fatigue, pain, sedentary lifestyle, and sleep disturbances that impact their daily living; however, little is known about the impact of these symptoms on mental health outcomes in these youth. This study addressed this gap and examined the individual and cumulative impacts of physiological symptoms on anxiety and depression symptoms in youth with CP. Forty youth with CP aged 8 to 18 years, and their caregiver, participated in this cross-sectional observational study. Pain, fatigue, anxiety, and depressive symptoms were measured using caregiver- and self-reported questionnaires and participants wore accelerometers for seven consecutive days, providing non-invasive physical activity and sleep pattern data. Youth with CP experienced substantial physiological symptoms and elevated anxiety and depression symptoms. Linear regression models determined that all physiological factors were predictive of caregiver-reported youth anxiety (R 2 = 0.23) and youth depressive symptoms (R 2 = 0.48). Fatigue, pain severity, sleep efficiency, and physical activity outcomes individually and cumulatively contributed to caregiver-reported youth anxiety and depression symptoms. These findings highlight the important role of physiological symptoms as potential risk factors and potential targets for intervention for mental health issues for in youth with CP. • Children with CP experienced pain, fatigue, disordered sleep, and low levels of physical activity. • Children with CP experienced elevated symptoms of anxiety and depression. • Linear regressions determined all physiological factors contributed to caregiver-related anxiety and depression symptoms. [ABSTRACT FROM AUTHOR]

Abstract: Cognitive changes in normal aging have been explained by the frontal-executive hypothesis, but the assumptions made by this hypothesis concerning the neurobiological causes are still a matter of debate. Executive functions (EF) may activate neural networks that include disparate grey matter regions, and rely on the integrity of white matter connections. In 118 adults (50–90 years old) from the GENIE study, white matter integrity was measured using diffusion tensor imaging, and information processing speed, fluid intelligence and EF were assessed. A theory-driven structural equation model was developed to test associations between variables. The model was revised, removing non-significant paths. The adjusted model explained well the covariance in our data; and suggested that the reduction in white matter integrity associated with age directly affected only working memory. Fluid intelligence was mediated by all measured cognitive variables. The results suggest that white matter integrity may be particularly important for abilities activating complex neural networks, as occurs in working memory. Integration of the information processing speed and frontal-executive hypotheses may provide important information regarding common, unique, and mediating factors in cognitive aging. [Copyright &y& Elsevier]