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Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The goal of the current study was to determine the extent to which atypical neural responsiveness during retaliation is associated with observed aggression in youth in residential care., Method: This functional magnetic resonance imaging study involved 83 adolescents (56 male and 27 female; mean age, 16.18 years) in residential care performing a retaliation task. Of the 83 adolescents, 42 displayed aggressive behavior within the first 3 months of residential care, whereas 41 did not. During the retaliation task, participants were offered either fair or unfair divisions of $20 pots (allocation phase) and could either accept the offer or reject it, and, by spending $1, $2, or $3, punish the partner (retaliation phase)., Results: The study's main findings were that aggressive adolescent showed the following: reduced down-regulation of activity within regions involved in representing the expected value of choice options (left ventromedial prefrontal cortex and left posterior cingulate cortex) as a function of offer unfairness and retaliation level; and reduced recruitment of regions implicated in response control (right inferior frontal gyrus and bilateral anterior insular cortex) and associated fronto-parietal regions as a function of retaliation level. The aggressive adolescents were also significantly more likely to have been aggressive prior to residential care and showed a strong trend for increased retaliation on the task., Conclusion: We suggest that individuals with a greater propensity for aggression show reduced representation of the negative consequences of retaliation and associated reduced recruitment of regions potentially involved in over-ruling these negative consequences to engage in retaliation., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex balance in the selection of non-human subjects. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: We explore patterns of childhood adversity (CA) in youth entering residential care. We also examine possible sex differences as well as the association between these patterns and key indicators of clinical functioning, including emotional problems, conduct problems, hyperactivity/inattention, prosocial behavior, peer problems, and trauma symptoms., Method: Data were obtained from archival records of 2,066 youth ( M age = 15.57, SD = 1.57) entering a family style residential program for the first time. The sample composition was: 65% boys, 45.8% White, 26.0% Black or African American, 12.5% Hispanic or Latino, 10.5% Multiracial, and 5.1% Other race. Inclusive latent class analysis was used to identify profiles of CA. Profile membership was used to examine sex differences and predict clinical functioning., Results: Five CA profiles were found: (1) Low Exposure, (2) Familial Dysfunction, (3) Neglect/Emotional Abuse, (4) High Exposure without Sexual Abuse, and (5) High Exposure with Sexual Abuse. Girls were more likely than boys to be in Neglect/Emotional Abuse and High Exposure with Sexual Abuse profiles. Each CA profile was associated with distinct clinical outcomes., Conclusions: This study highlights the importance of considering CA patterns when working with youth entering residential care. CA screening and classification during residential care admissions could better inform interventions for youth and their families and potentially improve the effectiveness of mental health services received. Future research should continue to study the connections between CA profiles and clinical outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Suicide is the third leading cause of death for individuals between 15 and 19 years of age. The high suicide mortality rate and limited prior success in identifying neuroimaging biomarkers indicate that it is crucial to improve the accuracy of clinical neural signatures underlying suicide risk. The current study implements machine-learning (ML) algorithms to examine structural brain alterations in adolescents that can discriminate individuals with suicide risk from typically developing (TD) adolescents at the individual level. Structural MRI data were collected from 79 adolescents who demonstrated clinical levels of suicide risk and 79 demographically matched TD adolescents. Region-specific cortical/subcortical volume (CV/SCV) was evaluated following whole-brain parcellation into 1000 cortical and 12 subcortical regions. CV/SCV parameters were used as inputs for feature selection and three ML algorithms (i.e., support vector machine [SVM], K-nearest neighbors, and ensemble) to classify adolescents at suicide risk from TD adolescents. The highest classification accuracy of 74.79% (with sensitivity = 75.90%, specificity = 74.07%, and area under the receiver operating characteristic curve = 87.18%) was obtained for CV/SCV data using the SVM classifier. Identified bilateral regions that contributed to the classification mainly included reduced CV within the frontal and temporal cortices but increased volume within the cuneus/precuneus for adolescents at suicide risk relative to TD adolescents. The current data demonstrate an unbiased region-specific ML framework to effectively assess the structural biomarkers of suicide risk. Future studies with larger sample sizes and the inclusion of clinical controls and independent validation data sets are needed to confirm our findings., (© 2023. The Author(s).)

Background: Irritability and anxiety frequently co-occur in pediatric populations. Studies separately looking at the neural correlates of these symptoms have identified engagement of similar neural systems - particularly those implicated in emotional processing. Both irritability and anxiety can be considered negative valence emotional states that might relate to emotion dysregulation . However, previous work has not examined the neural responding during the performance of an emotion regulation task as a function of interaction between irritability and anxiety simultaneously., Methods: This fMRI study involved 155 participants (90 with significant psychopathologies and 92 male) who performed the Affective Stroop Task, designed to engage emotion regulation as a function of task demands. The Affective Reactivity Index (ARI) was used to index irritability and the Screen for Child Anxiety Related Emotional Disorders (SCARED) was used to index anxiety., Results: Levels of irritability, but not anxiety, was positively correlated with responses to visual images within the right rostro-medial prefrontal cortex and left anterior cingulate cortex during view trials. The second region of ventral anterior cingulate cortex showed a condition-by-emotion-by-ARI score-by-SCARED score interaction. Specifically, anxiety level was significantly correlated with a decreased differential BOLD response to negative relative to neutral view trials but only in the presence of relatively high irritability ., Conclusions: Atypical maintenance of emotional stimuli within the rostro-medial prefrontal cortex may exacerbate the difficulties faced by adolescents with irritability. Moreover, increased anxiety combined with significant irritability may disrupt an automatic emotional conflict-based form of emotion regulation that is particularly associated with the ventral anterior cingulate cortex.

While neuro-cognitive work examining aggression has examined patients with conditions at increased risk for aggression or individuals self-reporting past aggression, little work has attempted to identify neuro-cognitive markers associated with observed/recorded aggression. The goal of the current study was to determine the extent to which aggression by youth in the first three months of residential care was associated with atypical responsiveness to threat stimuli. This functional MRI study involved 98 (68 male; mean age = 15.96 [sd = 1.52]) adolescents in residential care performing a looming threat task involving images of threatening and neutral human faces or animals that appeared to be either loom or recede. Level of aggression was negatively associated with responding to looming stimuli (irrespective of whether these were threatening or neutral) within regions including bilateral inferior frontal gyrus, right inferior parietal lobule, right superior/middle temporal gyrus and a region of right uncus proximal to the amygdala. These data indicate that aggression level is associated with a decrease in responsiveness to a basic threat cue-looming stimuli. Reduced threat responsiveness likely results in the individual being less able to represent the negative consequences that may result from engaging in aggression, thereby increasing the risk for aggressive episodes., (© The Author(s) 2021. Published by Oxford University Press.)

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Youth who receive services in residential programs have high rates of traumatic exposure and associated symptoms of Posttraumatic Stress Disorder (PTSD). Little information is available on specific social skills training that could be beneficial for youth in residential programs with PTSD. This study examined changes in behavioral incidents and psychopathology in youth receiving group home services based on training they received across three categories of social skills (i.e., self-advocacy, emotional regulation, problem-solving)., Method: The sample included archival data on youth ( N = 677) ages 10-18 years ( M = 15.7 years, SD = 1.53). Hierarchical Linear Modeling was used to examine the frequency of disruptive and self-injurious behaviors over 12 months as it relates to reported traumatic symptoms at admission and the presence of the three types of social skills objectives. Analysis of Covariance was conducted to test whether the social skill objectives differentially predicted changes in youth psychopathology from intake to discharge for youth with low and high trauma symptoms., Results: Youth with high trauma symptoms who received training on problem-solving skills had significantly greater decrease in emotional problems from intake to discharge compared to youth with high trauma symptoms who did not receive problem-solving training ( d = -.54)., Conclusion: Problem-solving training could be further developed and tested to maximize the support youth with trauma symptoms receive in trauma-informed residential programs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Two of the most commonly used substances by adolescents in the United States are cannabis and alcohol. Cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with impairments in decision-making processes. One mechanism for impaired decision-making in these individuals is thought to be an inability to adequately represent future events during decision-making. In the current study involving 112 adolescents, we used a comparative optimism task to examine the relationship between relative severity of CUD/AUD (as indexed by the CUD/AUD Identification Tests [CUDIT/AUDIT]) and atypical function within neural systems underlying affect-based neural represenation future events. Greater CUDIT scores were negatively related to responses within subgenual anterior and posterior cingulate cortex when processing high-intensity potential future positive and negative events. There was also a particularly marked negative relationship between CUD symptoms and blood oxygen level-dependent (BOLD) responses within visual and premotor cortices to high-intensity, negatively valenced potential future events. However, AUD symptom severity was not associated with dysfunction within these brain regions. These data indicate that relative risk/severity of CUD is associated with reduced responsiveness to future high-intensity events. This may impair decision-making where future significant consequences should guide response choice., (© 2020 Society for the Study of Addiction.)

Trauma-informed care is recommended to improve the quality of group home services for youth. Youth exposure to trauma and associated symptoms are important factors involved in making the clinical impression that determines treatment services. This study considered three dimensions of trauma (exposure, symptoms, and clinical impression) to determine associations with behavioral incidents of youth in trauma-informed group homes and how trauma was related to changes in psychopathology from intake to discharge. Archival records of youth (N = 1,096), age 9-18 (M = 15.7 years) who received services from January 2013 to December 2017, and departed the program were used. Statistical procedures included hierarchical linear modeling and analysis of covariance. Results indicated trauma symptoms predicted emotional problems and self-injurious behavior. Youth in high- and low-trauma groups both showed decreases in behavioral incidents and psychopathology, but clinical impression of trauma moderated the change in emotional problems from intake to discharge. Youth deemed by clinicians to have lower trauma (based on history of maltreatment and expression of trauma symptoms) had greater decrease in emotional problems from admission to discharge. Limitations and implications for further research on implementation and effectiveness of trauma-informed models are discussed., (© 2019 The Authors. American Journal of Community Psychology published by Wiley Periodicals, Inc. on behalf of Society for Community Research and Action.)

Despite extensive behavioral evidence of impairments in face processing and expression recognition in adults with alcohol or cannabis use disorders (AUD/CUD), neuroimaging findings have been inconsistent. Moreover, relatively little work has examined the relationship of AUD or CUD symptoms with face or expression processing within adolescents. Given the high prevalence of alcohol and cannabis use during adolescence, understanding how these usage behaviors interact with neural mechanisms supporting face and expression processing could have important implications for youth social and emotional functioning. In this study, adolescents (N = 104) responded to morphed fearful and happy expressions during fMRI and their level of AUD and/or CUD symptoms were related to the BOLD response data. We found that AUD and CUD symptom severity were both negatively related to responses to faces generally. However, whereas this relationship was shown for AUD within ventromedial prefrontal cortex and lingual gyrus, it was shown for CUD within rostromedial prefrontal cortex including anterior cingulate cortex. Additionally, AUD symptom levels were associated with differential responses within medial temporal pole and inferior parietal lobule as a function of expression. These results have potential implications for understanding the social and emotional functioning of adolescents with AUD and CUD symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Trauma screening is an important element for providing trauma-informed services to youth in residential care. Unfortunately, lack of time and resources may deter clinicians from conducting trauma screening at intake. This study tested the psychometric properties of the Brief Trauma Symptom Screen for Youth (BTSSY), which could be used during intake into residential care. Participants included 572 youth, ages 10-18 years (M = 14.28 years, SD = 2.31), of whom 58.9% were boys, 78.7% were Caucasian, 51.7% were youth receiving services in residential care, 15.6% were youth with clinical needs, and 32.7% were typically developing youth from the local community. Participants completed the BTSSY; other questionnaires of psychopathology, childhood maltreatment, and symptomology of posttraumatic stress disorder (PTSD); and diagnostic interviews, which were conducted by licensed psychiatrists. The total BTSSY score had a good composite reliability (CR) of .80 and was valid based on a significant positive correlation, r = .64, with the UCLA PTSD-Reaction Index. The BTSSY score was also fair, area under the curve = .75, at detecting a diagnosis of PTSD from a psychiatrist. Significant group differences in the BTSSY scores were found between youth with a diagnosis of PTSD and the other two groups, with moderate-to-large effect sizes, ds = 0.73-1.22. Preliminary results indicated the BTSSY may be a useful screening tool for identifying youth at residential care intake who may need additional assessment for PTSD. Limitations and implications for future research and practice are discussed., (© 2019 International Society for Traumatic Stress Studies.)

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.

Objective: Two of the most commonly abused substances by adolescents in the United States are alcohol and cannabis, both of which are associated with adverse medical and psychiatric outcomes throughout the lifespan. Both are assumed to impact the development of emotional processing although findings on the direction of this impact have been mixed. Preclinical animal work and some functional magnetic resonance imaging (fMRI) work with humans have suggested cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with increased threat responsiveness. However, other fMRI work has indicated CUD/AUD are associated with diminished threat responsiveness. In this study, we report on a study examining the relationship of severity of CUD/AUD and threat responsiveness in an adolescent population. Methods: The study involved 87 (43 male) adolescents with varying levels of CUD/AUD symptomatology ( N  = 45 above clinical cutoffs for CUD or AUD). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding. Results: Increasing levels of CUD symptomatology were associated with decreased responding to looming stimuli within regions, including rostral frontal and fusiform gyrus as well as the amygdala. There were no relationships with AUD symptomatology. Conclusions: These data indicate that CUD in particular is associated with a decrease in responsiveness to the looming threat cue possibly relating to the putative neurotoxic impact of cannabis abuse.

Importance: Childhood maltreatment is associated with serious developmental consequences that may be different depending on the form of maltreatment. However, relatively little research has investigated this issue despite implications for understanding the development of psychiatric disorders after maltreatment., Objective: To determine the association of childhood maltreatment and potential differential associations of childhood abuse or neglect with neural responsiveness within regions of the brain implicated in emotional responding and response control., Design, Setting, and Participants: In this cross-sectional study, participants aged 10 to 18 years with varying levels of prior maltreatment as indexed by the Childhood Trauma Questionnaire (CTQ) were recruited from a residential care facility and the surrounding community. Blood oxygen level-dependent response data were analyzed via 2 analyses of covariance that examined 2 (sex) × 3 (task condition [view, congruent, incongruent]) × 3 (valence [negative, neutral, positive]) with Blom-transformed covariates: (1) total CTQ score; and (2) abuse and neglect subscores. Data were collected from April 1, 2016, to June 30, 2018. Data analyses occurred from June 10, 2018, to October 31, 2018., Main Outcomes and Measures: Blood oxygenation level-dependent signals in response to an Affective Stroop task were measured via functional magnetic resonance imaging., Results: The sample included 116 youths (mean [SD] age, 15.0 [2.2] years; 70 [60.3%] male). Fifteen participants reported no prior maltreatment. The remaining 101 participants (87.1%) reported at least some prior maltreatment, and 55 (54.5%) reported significant maltreatment, ie, total CTQ scores were greater than the validated CTQ score threshold of 40. There were significant total CTQ score × task condition associations within the bilateral postcentral gyrus, left precentral gyrus, midcingulate cortex, middle temporal gyrus, and superior temporal gyrus (left postcentral gyrus: F = 11.73; partial η2 = 0.14; right postcentral and precentral gyrus: F = 9.81; partial η2 = 0.10; midcingulate cortex: F = 12.76; partial η2 = 0.12; middle temporal gyrus: F = 13.24; partial η2 = 0.10; superior temporal gyrus: F = 10.33; partial η2 = 0.11). In all examined regions of the brain, increased maltreatment was associated with decreased differential responsiveness to incongruent task trials compared with view trials (left postcentral gyrus: r = -0.34; 95% CI, -0.17 to -0.51; right postcentral and precentral gyrus: r = -0.31; 95% CI, -0.14 to -0.49; midcingulate cortex: r = -0.36; 95% CI, -0.18 to -0.53; middle temporal gyrus: r = -0.35; 95% CI, -0.17 to -0.52; superior temporal gyrus: r = -0.37; 95% CI, -0.20 to -0.55). These interactions were particularly associated with level of abuse rather than neglect. A second analysis of covariance revealed significant abuse × task condition (but not neglect × task) interactions within the midcingulate cortex (F = 13.96; partial η2 = 0.11), right postcentral gyrus and inferior parietal lobule (F = 15.21; partial η2 = 0.12), left postcentral and precentral gyri (F = 11.16; partial η2 = 0.12), and rostromedial frontal cortex (F = 10.36; partial η2 = 0.08)). In all examined regions of the brain, increased abuse was associated with decreased differential responsiveness to incongruent task trials compared with view trials (midcingulate cortex: partial r = -0.33; P < .001; right postcentral gyrus and inferior parietal lobule: partial r = -0.41; P < .001; left postcentral and precentral gyri: partial r = -0.40; P < .001; and rostromedial frontal cortex: partial r = -0.40; P < .001)., Conclusions and Relevance: These data document associations of different forms of childhood maltreatment with atypical neural response. This suggests that forms of maltreatment may differentially influence the development of psychiatric pathology.

Alcohol and cannabis are two of the most commonly used substances by adolescents and are associated with adverse medical and psychiatric outcomes. These adverse psychiatric outcomes may reflect the negative impact of alcohol and/or cannabis abuse on neural systems mediating reward and/or error detection. However, work indicative of this has mostly been conducted in adults with Alcohol and/or Cannabis Use Disorder (i.e., AUD and CUD), with relatively little work in adolescent patients. Furthermore, of the work that has been conducted in adolescents, groups were based on categorical diagnoses of AUD and/or CUD, so the relationship between AUD and/or CUD symptom severity in adolescents and neural dysfunction is unclear. We used a Monetary Incentive Delay (MID) task to examine the relationship between AUDIT and/or CUDIT scores and functional integrity of neuro-circuitries mediating reward processing and error detection within 150 adolescents. Our findings indicate that AUDIT score is negatively related to activity in reward processing neuro-circuitry in adolescents. However, CUDIT score is negatively related to activity in brain regions involved in error detection. Each of these relationships reflected a medium effect size (Partial-η 2 0.09-0.14). These data suggest differential impacts of AUD and CUD on reward versus error detection neuro-circuitries within the adolescent brain., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The functional significance of the impairment shown by patients with ADHD on response inhibition tasks is unclear. Dysfunctional behavioral and BOLD responses to rare no-go cues might reflect disruption of response inhibition (mediating withholding the response) or selective attention (identifying the rare cue). However, a factorial go/no-go design (involving high and low frequency go and no-go stimuli) can disentangle these possibilities., Methods: Eighty youths [22 female, mean age = 13.70 (SD = 2.21), mean IQ = 104.65 (SD = 13.00); 49 with diagnosed ADHD] completed the factorial go/no-go task while undergoing fMRI., Results: There was a significant response type-by-ADHD symptom severity interaction within the left anterior insula cortex; increasing ADHD symptom severity was associated with decreased recruitment of this region to no-go cues irrespective of cue frequency. There was also a significant frequency-by-ADHD symptom severity interaction within the left superior frontal gyrus. ADHD symptom severity showed a quadratic relationship with responsiveness to low frequency cues (irrespective of whether these cues were go or no-go); within this region, at lower levels of symptom severity, increasing severity was associated with increased BOLD responses but at higher levels of symptom severity, decreasing BOLD responses., Conclusion: The current study reveals two separable forms of dysfunction that together probably contribute to the impairments shown by patients with ADHD on go/no-go tasks., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

A cognitive neuroscience perspective seeks to understand behavior, in this case disruptive behavior disorders (DBD), in terms of dysfunction in cognitive processes underpinned by neural processes. While this type of approach has clear implications for clinical mental health practice, it also has implications for school-based assessment and intervention with children and adolescents who have disruptive behavior and aggression. This review articulates a cognitive neuroscience account of DBD by discussing the neurocognitive dysfunction related to emotional empathy, threat sensitivity, reinforcement-based decision-making, and response inhibition. The potential implications for current and future classroom-based assessments and interventions for students with these deficits are discussed.

T-cell priming occurs when a naïve T cell recognizes cognate peptide-MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8 + T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, we used transnuclear CD8 + T cells that recognize the melanoma antigen TRP1 using TRP1 high or TRP1 low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro , the K8 peptide induced robust proliferation of both TRP1 high and TRP1 low CD8 + T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor-bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9-stimulated cells produced more IFNγ, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8 + T cells., (©2018 American Association for Cancer Research.)

Background: Previous work has shown that amygdala responsiveness to fearful expressions is inversely related to level of callous-unemotional (CU) traits (i.e. reduced guilt and empathy) in youth with conduct problems. However, some research has suggested that the relationship between pathophysiology and CU traits may be different in those youth with significant prior trauma exposure., Methods: In experiment 1, 72 youth with varying levels of disruptive behavior and trauma exposure performed a gender discrimination task while viewing morphed fear expressions (0, 50, 100, 150 fear) and Blood Oxygenation Level Dependent responses were recorded. In experiment 2, 66 of these youth performed the Social Goals Task, which measures self-reports of the importance of specific social goals to the participant in provoking social situations., Results: In experiment 1, a significant CU traits-by-trauma exposure interaction was observed within right amygdala; fear intensity-modulated amygdala responses negatively predicted CU traits for those youth with low levels of trauma but positively predicted CU traits for those with high levels of trauma. In experiment 2, a bootstrapped model revealed that the indirect effect of fear intensity amygdala response on social goal importance through CU traits is moderated by prior trauma exposure., Conclusions: This study, while exploratory, indicates that the pathophysiology associated with CU traits differs in youth as a function of prior trauma exposure. These data suggest that prior trauma exposure should be considered when evaluating potential interventions for youth with high CU traits.

Alcohol and cannabis are two substances that are commonly abused by adolescents in the United States and which, when abused, are associated with negative medical and psychiatric outcomes across the lifespan. These negative psychiatric outcomes may reflect the detrimental impact of substance abuse on neural systems mediating emotion processing and executive attention. However, work indicative of this has mostly been conducted either in animal models or adults with Alcohol and/or Cannabis Use Disorder (AUD/CUD). Little work has been conducted in adolescent patients. In this study, we used the Affective Stroop task to examine the relationship in 82 adolescents between AUD and/or CUD symptom severity and the functional integrity of neural systems mediating emotional processing and executive attention. We found that AUD symptom severity was positively related to amygdala responsiveness to emotional stimuli and negatively related to responsiveness within regions implicated in executive attention and response control (i.e., dorsolateral prefrontal cortex, anterior cingulate cortex, precuneus) as a function of task performance. In contrast, CUD symptom severity was unrelated to amygdala responsiveness but positively related to responsiveness within regions including precuneus, posterior cingulate cortex, and inferior parietal lobule as a function of task performance. These data suggest differential impacts of alcohol and cannabis abuse on the adolescent brain.

Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL-2 increased the number of intratumoral CD8 + T cells, whereas IFNγ reduced the number of CD11b + cells and skewed intratumoral macrophages toward the display of M1-like characteristics. Imaging of fluorescent VHH-IFNγ constructs, as well as transcriptional profiling, demonstrated targeting of IFNγ to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy. Cancer Immunol Res; 6(4); 389-401. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-γ, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Vα14Jα18 TCRα paired with unique Vβ7 or Vβ8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORγt, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T-cell development and function. We determined the minimum concentration of selinexor required to block T-cell activation and showed that T-cell-inhibitory effects of selinexor occur at levels above 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ + , granzyme B + cytotoxic CD8 T cells that were comparable with vehicle-treated mice. Overall, selinexor treatment leads to transient inhibition of T-cell activation, but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T-cell functioning and development of antitumor immunity. Mol Cancer Ther; 16(3); 428-39. ©2017 AACR See related article by Farren et al., p. 417 ., (©2017 American Association for Cancer Research.)

Background: Previous work has shown that patients with conduct problems (CP) show impairments in reinforcement-based decision-making. However, studies with patients have not previously demonstrated any relationships between impairment in any of the neurocomputations underpinning reinforcement-based decision-making and specific symptom sets [e.g. level of CP and/or callous-unemotional (CU) traits]., Methods: Seventy-two youths [20 female, mean age = 13.81 (SD = 2.14), mean IQ = 102.34 (SD = 10.99)] from a residential treatment program and the community completed a passive avoidance task while undergoing functional MRI., Results: Greater levels of CP were associated with poorer task performance. Reduced representation of expected values (EV) when making avoidance responses within bilateral anterior insula cortex/inferior frontal gyrus (AIC/iFG) and striatum was associated with greater levels of CP but not CU traits., Conclusions: The current data indicate that difficulties in the use of value information to motivate decisions to avoid suboptimal choices are associated with increased levels of CP (though not severity of CU traits). Moreover, they account for the behavioral deficits observed during reinforcement-based decision-making in youth with CP. In short, an individual's relative failure to utilize value information within AIC/iFG to avoid bad choices is associated with elevated levels of CP., (© 2016 Association for Child and Adolescent Mental Health.)