Risk factors for depression in trauma-exposed children and adolescents: a systematic review and meta-analysis

Background: While Post Traumatic Stress Disorder (PTSD) has been the most frequently studied sequela in the aftermath of trauma, post-traumatic depression is at least as prevalent, if not more so. The impacts of depression are wide-ranging, deleterious and potentially long-term. Understanding the risk factors for post-traumatic depression in children and adolescents is therefore critical. The present systematic review and meta-analysis considered this question. Method: Three databases (Medline, PsycINFO, and Published International Literature on Traumatic Stress [PILOTS]) were searched for pertinent studies. Results: Fifty-seven studies (N = 45,981) allowed for the derivation of pooled effect sizes for 12 risk factors, contributing 145 effect sizes. All effect sizes were statistically significant. Negligible to small effect sizes were largely found for pre-trauma variables (age [r=0.09], gender [r=0.16], low family income [r=0.16] and prior trauma exposure [r=0.16) and trauma-related risk factors (trauma severity [r=0.20], peri‑traumatic distress [r=0.24] and direct exposure [r=0.07]). Small to large effect sizes were found for post-trauma variables (comorbid PTSD symptoms [r=0.58], avoidant coping [r=0.26], low social support [r=0.29] and maternal depression [r=0.20]) and bereavement (r=0.29). Limitations: Risk factor effect size estimates were characterised by significant heterogeneity, and several effect sizes were based on only a few studies (e.g. income, maternal depression). Conclusions: These findings suggest that the post-traumatic responses and environments of children and adolescents may be prominent risk factors for the emergence or maintenance of post-traumatic depression in children and adolescents. This highlights potential targets for assessment and monitoring those most at risk and may also inform treatment

Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation

Background While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway.Methods We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models.Results CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment (‘eat-me’) signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice.Conclusion Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses