Telomere Erosion and Depressive Symptoms Across Development Following Institutional Care.

OBJECTIVE: A large literature has identified exposure to early caregiving adversities as a potent risk for developing affective psychopathology, with depression, in particular, increasing across childhood into adolescence. Evidence suggests telomere erosion, a marker of biological aging, may underlie associations between adverse early-life experiences and later depressive behavior; yet, little is understood about this association during development. METHOD: The current accelerated longitudinal study examined concurrent telomere length and depressive symptoms concurrently, 2 and 4 years later, from the preschool period through adolescence among children exposed (n =116) and not exposed (n = 242) to early previous institutional (PI) care. RESULTS: PI care was associated with shorter telomeres on average and with quadratic age-related growth in depressive symptoms, indicating a steeper association between PI care and depressive symptoms in younger age groups that leveled off in adolescence. Contrary to studies in adult samples, telomere length was not associated with depressive symptoms, and it did not predict future symptoms. CONCLUSION: These findings indicate that early caregiving disruptions increase the risk for both accelerated biological aging and depressive symptoms, although these variables did not correlate with each other during this age range.

Longitudinal changes in amygdala, hippocampus and cortisol development following early caregiving adversity.

Although decades of research have shown associations between early caregiving adversity, stress physiology and limbic brain volume (e.g., amygdala, hippocampus), the developmental trajectories of these phenotypes are not well characterized. In the current study, we used an accelerated longitudinal design to assess the development of stress physiology, amygdala, and hippocampal volume following early institutional care. Previously Institutionalized (PI; N = 93) and comparison (COMP; N = 161) youth (ages 4-20 years old) completed 1-3 waves of data collection, each spaced approximately 2 years apart, for diurnal cortisol (N = 239) and structural MRI (N = 156). We observed a developmental shift in morning cortisol in the PI group, with blunted levels in childhood and heightened levels in late adolescence. PI history was associated with reduced hippocampal volume and reduced growth rate of the amygdala, resulting in smaller volumes by adolescence. Amygdala and hippocampal volumes were also prospectively associated with future morning cortisol in both groups. These results indicate that adversity-related physiological and neural phenotypes are not stationary during development but instead exhibit dynamic and interdependent changes from early childhood to early adulthood.

Parent's anxiety links household stress and young children's behavioral dysregulation.

Young children rely heavily on their caregivers to gain information about the environment, especially during times of duress. Therefore, considering parental assessments of behavior in the context of stressful environments may better facilitate our understanding of the longstanding association between early environmental stressors and changes in child behavior and physiology. Confirming many previous reports, a higher degree of household stress exposure was associated with elevated mental health symptoms in 2- to 6-year-old children (N = 115; anxiety and externalizing behaviors), which were verified in a subset of children with laboratory-based behaviors (N = 46). However, these associations were mediated by parental anxiety symptoms, which were also associated with increased cortisol levels in children. A closer look at the stressors indicated that it was the adult-targeted, and not the child-targeted, stressors that correlated most with children's behavior problems. These results highlight the importance of considering the mediating effect of parents, when examining associations between household stress and young children's behavioral development.

A Pilot Study of Radiation Therapy in Combination With Pembrolizumab in Patients With Metastatic Renal Cell Cancer.

OBJECTIVES: There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors. MATERIALS AND METHODS: mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. RESULTS: Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92). CONCLUSION: Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.

Predicting distracted driving: The role of individual differences in working memory.

The present study investigated the role of working memory capacity (WMC) in predicting distracted driving performance using a working memory distractor. Forty-nine participants (including one with missing data) completed four working memory complex spans prior to completing a distracted and non-distracted simulated driving trial. During the distracted driving trial, participants drove while simultaneously completing the grocery list task (GLT), a semi-naturalistic working memory task developed by the authors. Results showed that participants were significantly slower at braking when a yellow traffic light appeared and during sudden braking events when distracted. Furthermore, the impairing effect of distraction on braking response time was partially mediated by WMC. There was also a trend towards a moderating effect of WMC, where the impairing effect of distraction was more pronounced for individuals with low WMC than high WMC. Theoretical and practical implications for the role of individual differences in cognition and driving, in-vehicle devices use and traffic safety, as well as semi-autonomous vehicle design are also discussed.

Evaluating Circumplex Structure in the Interpersonal Scales for the NEO-PI-3.

Scales to assess the eight octants and two axes of the interpersonal circumplex (IPC) using items from the revised NEO Personality Inventory were introduced by Traupman et al. Item changes in the revised and renormed third edition of the NEO instrument (NEO-PI-3) have affected item content in all eight octant scales, underscoring the need to reexamine the IPC scales. The current study examines the circumplex structure of the revised octant scales in the NEO-PI-3 and their correlations with the Dominance and Warmth scales of the Personality Assessment Inventory in 568 undergraduate students. The data show perfect fit to circumplex structure, suggesting equivalent or better assessment of the IPC with the NEO-PI-3 octant scales. Convergence of the eight octants with the Personality Assessment Inventory interpersonal scales further supports their saturation with interpersonal content and appropriate location within the IPC.

Diurnal cortisol after early institutional care-Age matters.

Several studies have shown that young children who have experienced early caregiving adversity (e.g. previously institutionalization (PI)) exhibit flattened diurnal cortisol slopes; however, less is known about how these patterns might differ between children and adolescents, since the transition between childhood and adolescence is a time of purported plasticity in the hypothalamic-pituitary-adrenal (HPA) axis. PI youth experience a massive improvement in caregiving environment once adopted into families; therefore we anticipated that a developmental increase in HPA axis plasticity during adolescence might additionally allow for an enhanced enrichment effect by the adoptive family. In a cross-sectional sample of 197 youths (PI and Comparison; 4-15 years old) we observed age-related group differences in diurnal slope. First replicating previous findings, PI children exhibited flattened diurnal slope. This group difference, however, was not observed in adolescents. Moderation analyses showed that pubertal development, increased time with family, and early adoption contributed to the steeper diurnal cortisol slope in PI adolescents. These findings add support to existing theories positing that the transition between middle childhood and adolescence may mark an additional sensitive period for diurnal cortisol patterning, allowing PI youth to benefit from the enriched environment provided by adoptive parents during this period of development.

Positive valence bias and parent-child relationship security moderate the association between early institutional caregiving and internalizing symptoms.

Institutional caregiving is associated with significant deviations from species-expected caregiving, altering the normative sequence of attachment formation and placing children at risk for long-term emotional difficulties. However, little is known about factors that can promote resilience following early institutional caregiving. In the current study, we investigated how adaptations in affective processing (i.e., positive valence bias) and family-level protective factors (i.e., secure parent-child relationships) moderate risk for internalizing symptoms in previously institutionalized (PI) youth. Children and adolescents with and without a history of institutional care performed a laboratory-based affective processing task and self-reported measures of parent-child relationship security. PI youth were more likely than comparison youth to show positive valence biases when interpreting ambiguous facial expressions. Both positive valence bias and parent-child relationship security moderated the association between institutional care and parent-reported internalizing symptoms, such that greater positive valence bias and more secure parent-child relationships predicted fewer symptoms in PI youth. However, when both factors were tested concurrently, parent-child relationship security more strongly moderated the link between PI status and internalizing symptoms. These findings suggest that both individual-level adaptations in affective processing and family-level factors of secure parent-child relationships may ameliorate risk for internalizing psychopathology following early institutional caregiving.

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy.

BACKGROUND: Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient's own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20-40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment. Because radiotherapy has immunomodulatory effects on the tumor microenvironment, it has the potential to synergize with immunotherapy and augment tumor response. NCT02318771 is a phase 1 clinical trial designed to investigate the immunomodulatory effects of radiation therapy in combination with pembrolizumab. CASE PRESENTATION: The patient is a 64-year-old male with metastatic clear cell renal cell carcinoma, Fuhrman grade 4, pathologically staged as T3 N0. Metastatic disease was well controlled for several years with sunitinib. Following disease progression, he was switched to axitinib. When disease progression continued, the patient was enrolled in NCT02318771, a phase 1 clinical trial combining radiotherapy and pembrolizumab. The patient experienced unusually rapid disease progression during treatment, which was confirmed by repeated CT scans to rule out pseudoprogression. Tissue biopsies and peripheral blood draws were obtained before, during, and after treatment. Samples were analyzed to provide plausible rationale for rapid treatment failure. CONCLUSIONS: Biomarker analysis demonstrated an absence of TILs, which may be a cause of treatment failure as pembrolizumab works through T cell-dependent mechanisms. Furthermore, the presence of other non-redundant immune checkpoints in the periphery and tumor microenvironment presents a treatment challenge. Additionally, the radiation dose and fractionation schedule may have played a role in treatment failure as these factors play a role in the effect radiotherapy on the tumor microenvironment as well as the potential for synergy with immunotherapy. TRIAL REGISTRATION: An Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer, NCT02318771 .

Discrimination of amygdala response predicts future separation anxiety in youth with early deprivation.

BACKGROUND: Significant disruption in caregiving is associated with increased internalizing symptoms, most notably heightened separation anxiety symptoms during childhood. It is also associated with altered functional development of the amygdala, a neurobiological correlate of anxious behavior. However, much less is known about how functional alterations of amygdala predict individual differences in anxiety. Here, we probed amygdala function following institutional caregiving using very subtle social-affective stimuli (trustworthy and untrustworthy faces), which typically result in large differences in amygdala signal, and change in separation anxiety behaviors over a 2-year period. We hypothesized that the degree of differentiation of amygdala signal to trustworthy versus untrustworthy face stimuli would predict separation anxiety symptoms. METHODS: Seventy-four youths mean (SD) age = 9.7 years (2.64) with and without previous institutional care, who were all living in families at the time of testing, participated in an fMRI task designed to examine differential amygdala response to trustworthy versus untrustworthy faces. Parents reported on their children's separation anxiety symptoms at the time of scan and again 2 years later. RESULTS: Previous institutional care was associated with diminished amygdala signal differences and behavioral differences to the contrast of untrustworthy and trustworthy faces. Diminished differentiation of these stimuli types predicted more severe separation anxiety symptoms 2 years later. Older age at adoption was associated with diminished differentiation of amygdala responses. CONCLUSIONS: A history of institutional care is associated with reduced differential amygdala responses to social-affective cues of trustworthiness that are typically exhibited by comparison samples. Individual differences in the degree of amygdala differential responding to these cues predict the severity of separation anxiety symptoms over a 2-year period. These findings provide a biological mechanism to explain the associations between early caregiving adversity and individual differences in internalizing symptomology during development, thereby contributing to individualized predictions of future clinical outcomes.

Cultural differences in the links between parental control and children's emotional expressivity.

Research suggests that parental control may be motivated by various socialization goals and contributes to children's adjustment in diverse ways depending on cultural context. The present study examined whether parental psychological control was differentially related to children's emotional expressivity in a sample of 127 Korean, Asian American (AA), and European American (EA) preschoolers. Results indicated that Korean and AA parents endorsed more parental control (emotion suppression, shaming) than EA parents. Similarly, Korean and AA children displayed less observable sadness and exuberance during emotion-eliciting tasks than EA children. Furthermore, moderation analyses revealed that for EA families, parental control was positively correlated with child anger and exuberance; however, the associations were not significant for AA and Korean families.

Cultural differences in daily support experiences.

Previous research has suggested that Asian Americans (AAs) are less likely to mobilize social support, and find support to be less helpful, when compared with European Americans (EAs). In a 10-day daily diary study of AA and EA college students, we hypothesized that AAs would activate support less frequently than EAs for both stressful and positive events, a cultural difference that would be mediated by group harmony values. We also predicted that AAs would find support to be less helpful, and we explored differences in the sources of support used. Results confirmed that cultural differences in support use were partially mediated by the value of maintaining group harmony through emotional restraint. AAs also perceived received support to be less helpful and more frequently used discretionary rather than kinship support sources. Findings suggest that naturalistic support experiences differ markedly for these groups, with implications for help-seeking behavior and mental health services.

Learning what feelings to desire: socialization of ideal affect through children's storybooks.

Previous findings suggest that cultural factors influence ideal affect (i.e., the affective states that people ideally want to feel). Three studies tested the hypothesis that cultural differences in ideal affect emerge early in life and are acquired through exposure to storybooks. In Study 1, the authors established that consistent with previous findings, European American preschoolers preferred excited (vs. calm) states more (indexed by activity and smile preferences) and perceived excited (vs. calm) states as happier than Taiwanese Chinese preschoolers. In Study 2, it was observed that similar differences were reflected in the pictures (activities, expressions, and smiles) of best-selling storybooks in the United States and Taiwan. Study 3 found that across cultures, exposure to exciting (vs. calm) storybooks altered children's preferences for excited (vs. calm) activities and their perceptions of happiness. These findings suggest that cultural differences in ideal affect may be due partly to differential exposure to calm and exciting storybooks.

Proteasome function and protein oxidation in the aged retina.

The proteasomal pathway is responsible for processes essential for cell viability, including the selective degradation of oxidized proteins. An age-dependent loss in proteasome function has been reported in many tissues, but has not been examined in the retina. In this study, we evaluated proteasome function and protein oxidation in retinal homogenates from young adult and old F344BN rats. For retinal proteasome from old rats, we observed an 80% decrease in the rate of casein degradation and a 75% loss in chymotrypsin-like activity. This loss in activity could be partially accounted for by a 50% reduction in expression of the 20S proteasome. The regulatory complex PA700 and the inducible beta-subunit, LMP7, which is associated with the chymotrypsin-like activity, were expressed in equivalent concentrations relative to the 20S catalytic core in both young and old rats. Immunochemical analysis using antibodies that recognize the protein oxidative modifications, nitrotyrosine and 4-hydroxy-2-nonenal, showed that retinal proteins from old rats exhibited the greatest immunoreactivity. These results suggest that the age-related loss in proteasome function contributes to the accumulation of oxidized retinal proteins. Thus, the combined effect of an increase in oxidized proteins and inactivation of the protease responsible for ridding the cell of oxidized proteins places the aged retina at greater risk for irreversible damage caused by oxidative stress.

Localization of arm representation in the corona radiata and internal capsule in the non-human primate.

Localization of the corticofugal projection in the corona radiata (CR) and internal capsule (IC) can assist in evaluating a patient's residual motor capacity following subtotal brain damage and predicting their potential for functional restitution. To advance our understanding of the organization of the corticofugal projection in this critical brain region, we studied the trajectories of the projection arising from six different cortical arm representations in rhesus monkeys. They included the arm representation of the primary (M1), ventral lateral pre- (LPMCv), dorsolateral pre- (LPMCd), supplementary (M2), rostral cingulate (M3) and caudal cingulate (M4) motor cortices. In the CR, each pathway was segregated as medial motor area fibres arched over the caudate and lateral motor area fibres arched over the putamen. In the IC, the individual corticofugal pathways were found to be widespread, topographically organized and partially overlapping. At superior levels of the IC, the corticofugal projection from the arm representation of M3 coursed through the middle and posterior portion of the anterior limb (ICa). The projection from M2 passed through the posterior portion of the ICa and the genu (ICg). The projection from LPMCv travelled through the genu and anterior portion of the posterior limb (ICp). The projection from LPMCd occupied the anterior portion of the ICp. The projection from M4 descended through the mid-portion of the ICp. Fibres from M1 also travelled in the ICp, positioned immediately posterior to the M4 projection. As each fibre system progressed inferiorly within the IC, all fibres shifted posteriorly to occupy the ICp. Within the ICp, the projections from M3, M2, LPMCv, LPMCd, M4 and M1 maintained their anterior to posterior orientation, respectively. M2, LPMCd and LPMCv fibres overlapped extensively, as did fibres from M4 and M1. Our data suggest that CR and superior capsular lesions may correlate with more favourable levels of functional recovery due to the widespread nature of arm representation. In contrast, the extensive overlap and comparatively condensed organization of arm representation at inferior capsular levels suggest that lesions seated inferiorly are likely to correlate with poorer levels of recovery of upper limb movement. Based on the relative density of corticospinal neurones associated with the motor areas studied, our findings also suggest that motor deficit severity is likely to increase as a lesion occupies progressively more posterior regions of the IC.