Early life stress and macaque annygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene

Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. the primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: high cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.National Institute for Mental HealthNIMHNARSAD Mid-investigator AwardSuny Downstate Med Ctr, Dept Psychiat & Behav Sci, Brooklyn, NY 11203 USAUniversidade Federal de São Paulo, Dept Psiquiatria, São Paulo, BrazilMt Sinai Sch Med, Dept Psychiat, New York, NY USAMt Sinai Sch Med, Dept Neurosci, New York, NY USAMt Sinai Sch Med, Dept Radiol, New York, NY USANew York State Psychiat Inst & Hosp, New York, NY 10032 USAMichael E Debakey VA Med Ctr, Mental Hlth Care Line, Houston, TX USABaylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USAYale Univ, Sch Med, Dept Psychiat, New Haven, CT USANatl Ctr PTSD, Clin Neurosci Div, West Haven, CT USANew York State Psychiat Inst & Hosp, Dept Mol Imaging & Neuropathol, New York, NY 10032 USAColumbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USAColumbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USAComprehensive NeuroSci Corp, Westchester, NY USAUniv Miami Hlth Sytems, Dept Psychiat & Behav Sci, Miami, FL USAEmory Univ, Sch Med, Dept Psychiat & Behav Sci, Emory, GA USAUniversidade Federal de São Paulo, Dept Psiquiatria, São Paulo, BrazilNational Institute for Mental Health: R01MH65519-01National Institute for Mental Health: R01MH098073NIMH: R21MH066748NIMH: R01MH59990AWeb of Scienc

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants

Novel cytokine–antibody fusion protein, N-820, to enhance the functions of ex vivo expanded natural killer cells against Burkitt lymphoma

Background The prognosis of patients with relapsed or progressive B cell (CD20+) non-Hodgkin’s lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemoradiotherapy resistance. Novel therapeutic strategies are urgently needed. N-820 is a fusion protein of N-803 (formerly known as ALT-803) to four single-chains of rituximab. This agent has tri-specific binding activity to CD20 and enhanced antibody-dependent cell-mediated cytotoxicity.Methods We investigated the anti-tumor combinatorial effects of N-820 with ex vivo expanded peripheral blood natural killer (exPBNK) cells against rituximab-sensitive and rituximab-resistant CD20+ BL in vitro using cytoxicity assays and in vivo using human BL xenografted NOD/SCID/IL2rγnull (NSG) mice. We also investigated the cytokines/chemokines/growth factors released using ELISA and multiplex assay. Gene expression changes were examined using real-time PCR arrays.Results N-820 significantly enhanced the expression of NK activating receptors (p<0.001) and the proliferation of exPBNK cells with enhanced Ki67 expression and Stat5 phosphorylation (p<0.001). N-820 significantly enhanced the secretion of cytokines, chemokines, and growth factors including GM-CSF, RANTES, MIP-1B (p<0.001) from exPBNK cells as compared with the combination of rituximab+N-803. Importantly, N-820 significantly enhanced in vitro cytotoxicity (p<0.001) of exPBNK with enhanced granzyme B and IFN-γ release (p<0.001) against BL. Gene expression profiles in exPBNK stimulated by N-820+Raji-2R showed enhanced transcription of CXCL9, CXCL1, CSF2, CSF3, GZMB, and IFNG. Moreover, N-820 combined with exPBNK significantly inhibited rituximab-resistant BL growth (p<0.05) and extended the survival (p<0.05) of BL xenografted NSG mice.Conclusions Our results provide the rationale for the development of a clinical trial of N-820 alone or in combination with endogenous or ex vivo expanded NK cells in patients with CD20+ B-NHL failing prior rituximab containing chemoimmunotherapy regimens

An Argument for Adolescent and Young Adult Cancer Registry: One Model

Over the last several years, there has been increasing awareness around the unique challenges faced by adolescent and young adult (AYA) cancer patients. More cancer centers across the United States are introducing AYA-specific programs to help improve outcomes for these patients. However, given the nature of the United States health care system, there is little ability to track the efficacy of these programs and identify important variables with respect to both interdisciplinary interventions offered and medical and psychosocial outcomes. One program offers an argument as to why tracking these data is important, with a description of the registry they have developed

Cerebrospinal Fluid Concentrations of Somatostatin and Biogenic Amines in Grown Primates Reared by Mothers Exposed to Manipulated Foraging Conditions

BACKGROUND In an earlier study, infant primates were nursed by mothers randomly assigned to variable foraging demand (VFD) or nonvariable foraging conditions (non-VFD). A group of grown VFD-reared subjects demonstrated elevations of cisternal cerebrospinal fluid (CSF) corticotropin-releasing factor concentrations and decreased CSF cortisol levels vs non-VFD counterparts. To further characterize neurobiological sequelae of disturbed early rearing, CSF concentrations of serotonin, dopamine, and norepinephrine metabolites (5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol [MHPG], respectively) and of somatostatin were determined. METHODS Second CSF taps were obtained from the previously studied cohort of 30 subjects and from 28 age-matched ad libitum–reared control subjects. Relevant assays were performed. RESULTS All neurochemicals assayed except MHPG were elevated in the VFD-reared compared with non-VFD subjects. In the VFD group, statistically significant positive correlations between corticotropin-releasing factor and each neurochemical was found, except for MHPG. In the non-VFD subjects, no significant correlations with corticotropin-releasing factor were observed. No effect of age was evident. CONCLUSIONS Reducing the predictability of maternal foraging demand during early rearing was associated with elevations of cisternal somatostatin and of serotonin and dopamine metabolite concentrations in grown offspring. The corticotropin-releasing factor elevations reported previously were positively correlated with all the elevated CSF parameters of the current study. The findings support the notion that adverse early rearing experiences in primates have longstanding and complex effects on a range of neurochemicals relevant to emotional regulation. Replication in prospective age-controlled studies is warranted.Arch Gen Psychiatry. 1998;55:473-477--

Combinatorial Immunotherapy of N-803 (IL-15 Superagonist) and Dinutuximab with Ex Vivo Expanded Natural Killer Cells Significantly Enhances in Vitro Cytotoxicity against GD2

BACKGROUND: Children with recurrent and/or metastatic osteosarcoma (OS), neuroblastoma (NB) and glioblastoma multiforme (GBM) have a dismal event-free survival ( METHODS: The anti-tumor combinatorial effects of N-803, dinutuximab and ex vivo expanded peripheral blood NK cells (exPBNK) were performed in vitro using cytoxicity assays against GD2 RESULTS: N-803 increased the viability and proliferation of exPBNK. The increased viability and proliferation are associated with increased phosphorylation of Stat3, Stat5, AKT, p38MAPK and the expression of NK activating receptors. The combination of dinutuximab and N-803 significantly enhanced in vitro cytotoxicity of exPBNK with enhanced perforin and IFN-γ release against OS, GBM and NB. The combination of exPBNK+N-803+dinutuximab significantly reduced the secretion of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), platelet-derived growth factor-BB (PDGF-BB), and stem cell growth factor beta (SCGF-β) from OS or GBM tumor cells. Furthermore, OS or GBM significantly inhibited the secretion of regulated on activation, normal T cell expressed and presumably secreted (RANTES) and stromal cell-derived factor-1 alpha (SDF-1α) from exPBNK cells (p CONCLUSIONS: Our results provide the rationale for the development of a clinical trial of N-803 in combination with dinutuximab and ex vivo exPBNK cells in patients with recurrent or metastatic GD2+ solid tumors

Protein phosphatase 1 regulatory subunit 1A regulates cell cycle progression in Ewing sarcoma

Introduction: We recently identified protein phosphatase 1 regulatory subunit 1A (PPP1R1A) as oneof the EWS/FLI core targets that promotes tumor growth and metastasis in Ewing sarcoma (ES), an aggressive pediatric bone and soft tissue tumor. In the current study, we seek to further define the role of PPP1R1A in ES and identify rational combinatorial therapy with improved and specific efficacy in treating primary and metastatic ES. Experimental design: We evaluated ES cell proliferation and cell cycle progression in control and PPP1R1A depleted ES cells. PPP1R1A regulation of cell cycle modulators was analyzed to characterize the underlying mechanism of PPP1R1A mediated cell cycle control. The effects of combination of PPP1R1A and IGF-1R inhibition on ES cell viability and migration in vitro as well as tumor growth and metastasis in an orthotopic xenograft mouse model were investigated. Results: PPP1R1A regulates ES cell cycle in G1/S phase by down-regulating cell cycle inhibitors p21Cip1 and p27Kip1 which results in Rb protein hyperphosphorylation and by promoting normal transcription of replication-dependent histone genes. Furthermore, the combination of PPP1R1A and IGF-1R inhibition induced a synergistic/additive effect on decreasing cell proliferation and migration in vitro and xenograft tumor growth and metastasis in vivo. Conclusions: Taken together, our findings suggest a role of PPP1R1A as an ES specific cell cycle modulator and that simultaneous targeting of PPP1R1A and IGF-1R pathways is a promising specific and effective strategy to treat both primary and metastatic ES

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates

Background: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. Methods: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. Results: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. Conclusions: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature

Differing concentrations of corticotropin-releasing factor and oxytocin in the cerebrospinal fluid of bonnet and pigtail macaques

The two neuropeptides corticotropin-releasing-factor (CRF) and oxytocin (OT) may produce opposing behavioral effects — elevations of the former have been associated with anxiety and social vigilance and reductions of the latter with reduced social affiliation. We sought to test the hypothesis that, within the primate macaque genus, the more gregarious, affiliative, and affectively stable bonnet species ( Macaca radiata) would exhibit lower cerebrospinal fluid (CSF) CRF and higher CSF OT concentrations in comparison to its close relative, the temperamentally volatile and socially distant pigtail ( Macaca nemestrina). Cisternal CSF samples were obtained from young adult male and female pigtail and bonnet macaques, and CRF and OT concentrations were measured by radioimmunoassay. Pigtail macaques exhibited significantly higher concentrations of CSF CRF and significant lower concentrations of CSF OT than bonnet macaques. Results were not attributable to age or sex differences in group composition. When included together in a multiple regression, CRF and OT showed a multiple R of 0.76, accounting for more than half of the species variance. Although species differences in the bioeffectiveness of these peptides may possibly confound the observed biobehavioral relationships, in the absence of any existing data to that effect, the current findings appear in accordance with the hypothesis and consistent with previously reported species–typical behaviors observed in these macaques