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PD-1/PD-L1 protein complex is attracting a great deal of interest as a drug target for the design of immune therapies able to block its assembly. Although some biologic drugs have entered clinical use, their poor response rate in patients are demanding further efforts to design small molecule inhibitors of PD-1/PD-L1 complex with higher efficacy and optimal physicochemical properties. Dysregulation of pH in the tumor microenvironment is indeed one of the key mechanisms promoting drug resistance and lack of response in cancer therapy. Integrating computational and biophysical approaches, herein we report a screening campaign that has led to identifying VIS310 as a novel ligand of PD-L1, with physicochemical properties enabling a pH-dependent binding potency. Additional optimization efforts by analogue-based screening have been instrumental to disclosing VIS1201, which exhibits improved binding potency against PD-L1 and is able to inhibit PD-1/PD-L1 complex formation in a ligand binding displacement assay. While providing preliminary structure-activity relationships (SARs) of a novel class of PD-L1 ligands, our results lay the foundation for the discovery of immunoregulatory small molecules resilient to tumor microenvironmental conditions for escaping drug-resistance mechanisms.

Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns.

We provide a conceptual model on the complex interaction between stress, psychological predisposition, and personality traits, accounting for gender, in parents of children with and without autism. We performed a path analysis using a structural equation modeling approach in a sample of parents including 60 ASD and 53 TD couples. In parents of typically developing children (TD), depression level and age are the main direct predictors of stress through the mediating effect of anxiety. Otherwise, in the ASD parent group, the personality trait 'openness' directly predicts the defensive response and stress levels without the mediating effect of anxiety. Our data suggest a route of action in promoting new behavioral strategies to prevent parenting stress, making families run smoothly.

Background: Acceptance and Commitment Therapy (ACT) has been demonstrated as effective in improving psychological well-being in several clinical domains, but there is no evidence regarding the parents of children with Autism Spectrum Disorder (ASD)., Methods: In this randomized controlled trial, we evaluated the efficacy of the ACT matrix behavioral protocol in comparison to the Parent Training (PT) program, measuring several primary and secondary outcomes prior to and following treatments. Twelve parents were randomly and equally assigned to two demographically matched groups wherein individuals underwent 24 weekly meetings of ACT protocol (experimental group) or conventional PT (control group)., Results: Parents enrolled in the ACT protocol demonstrated significant improvement in psychological flexibility, awareness states, personal values in everyday life, and parental stress, whereas reduced scores were elicited in parents' perceptions of their child's disruptive behaviors., Conclusions: The results of this randomized controlled trial, if repeated with a large number of subjects, could open the way to include ACT protocols in daily practice to support the development of new parenting skills.

Background: Recently, there has been an increased interest in the efficacy of mindfulness-based interventions (MBI) for people with cardiovascular diseases (CVD), although the exact beneficial effects remain unclear., Methods: This review aims to establish the role of MBI in the management of wellbeing for patients with CVD. Seventeen articles have been included in this systematic synthesis of the literature and eleven in the meta-analysis., Results: Considering physical (i.e., heart rate, blood pressure) and psychological outcomes (i.e., depression, anxiety, stress, styles of coping), the vast majority of studies confirmed that MBI has a positive influence on coping with psychological risk factors, also improving physiological fitness. Random-effects meta-analysis models suggested a moderate-to-large effect size in reducing anxiety, depression, stress, and systolic blood pressure., Conclusions: Although a high heterogeneity was observed in the methodological approaches, scientific literature confirmed that MBI can now be translated into a first-line intervention tool for improving physical and psychological wellbeing in CVD patients., Competing Interests: The authors declare no conflict of interest.

Background: Telehealth is useful for both autism spectrum disorder (ASD) diagnosis and treatment, but studies with a direct comparison between teletherapy and traditional in-person therapy are limited., Methods: This randomized control trial-ISRCTN (International Standard Randomised Controlled Trial Number) primary clinical trial registry ID ISRCTN15312724-was aimed at comparing the effect of a tele-assisted and in-person intervention based on a behavioral intervention protocol for families with children affected by ASDs. Forty-two parents with children with autism (30 months to 10 years old) were randomly assigned to 12 sessions of an applied behavioral analysis (ABA) intervention implemented in an individual and group setting, either with or without the inclusion of tele-assistance. Pre- and postintervention assessments were conducted using the Home Situation Questionnaire (HSQ-ASD) and the Parental Stress Index (PSI/SF)., Results: Substantial improvements in the perception and management of children's behavior by parents, as well as in the influence of a reduction in parent stress levels on said children's behavior through the use of a tele-assisted intervention, were obtained., Conclusions: This randomized controlled trial demonstrates the evidence-based potential for telehealth to improve treatment of ASDs.

In our study, we explored the construct of alexithymia in parents of children with and without ASD using a multi-method approach based on self-rated and external rater assessment. We also assessed the level of self-report measures of negative affect states such as trait anxiety and depression, and investigated the correlation between the alexithymia construct, trait anxiety, and depression within the broader autism phenotype (BAP). A total sample of 100 parents (25 mothers and 25 fathers in each group) were administered the TAS-20 and the TSIA to measure self-reported and observer-rated alexithymia traits, as well as self-report measures of anxiety and depression. Study results showed that the TSIA but not the TAS-20 was able to detect significant group differences in alexithymia traits among parents of children with and without ASD, with parents of ASD children displaying significantly higher levels of alexithymia. Furthermore, differently from the TAS-20, no significant correlations between the TSIA and measures of anxiety and depression were detected. Taken together, our results suggest the importance of using multi-method approaches to control for potential measurement bias and to detect psychological constructs such as alexithymia in subclinical samples such as parents of children with ASD.