BackgroundWhile 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.MethodsWe 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.ResultsCI-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.ConclusionTogether, 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.

Background: Preterm premature rupture of membranes (PPROM) is spontaneous rupture of the fetal membranes before 37 completed weeks and before onset of labour which complicates 3-5% of all pregnancies. Studies regarding PPROM in very early gestation are lacking. The primary objective was to assess the maternal and perinatal outcome in preterm premature rupture of membranes and secondary objective was to assess the colonization of group B Streptococci (GBS) and Listeria monocytogenes in patients with PPROM.Methods: This prospective study was performed on 175 antenatal women with PPROM between 24 to 34 weeks of gestation.Results: Majority of women (54.2%) were between 32 to 34 weeks of gestation, 37% were between 28 to 32 weeks of gestation and 7.8% were between 24 to 28 weeks of gestation. About 22 % of women had cervicovaginal infections. The prevalence of group B Streptococci in the study group was 1.2% and no isolates of Listeria. The most common maternal morbidity was puerperal fever (11.4 %). Among newborn babies 87 (55 %) required neonatal intensive care unit (NICU) admission mainly for respiratory distress and prematurity. With each week of increase in gestational age, there is decrease in latency period by 22 hours and duration of NICU stay nearly by one day.Conclusions: From the present study it may be concluded that PPROM is associated with genitourinary infection, puerperal pyrexia and respiratory distress syndrome among neonates. The prevalence of group B Streptococci in antenatal women with PPROM is very low and no Listeria were isolated.

Medulloblastoma is the most common type of malignant brain tumor that afflicts children. Although cisplatin chemotherapy and radiation have been the cornerstones of medulloblastoma intervention for over 20 years, the outcomes of these highly cytotoxic treatments are far from optimal, and there is increasing evidence that they cause long-term problems such as neurocognitive deficits and secondary tumors, even in patients with a good initial response. Thus, there is a critical need for more effective therapies to combat this disease. To approach this problem we investigated protein kinase function in medulloblastoma using RNAi combined with genomic methods. First, we performed a kinome-wide siRNA screen and identified a cohort of genes that mediates medulloblastoma cell viability. These include a signaling node of kinases that are key components of the G2-M transition including, Aurora Kinase A, Aurora Kinase B, Plk1, Wee1, Nek2 and Mps1. Clearly the G2-M transition is critical for medulloblastoma cells, so kinases required for the process are potentially important therapeutic targets. We subsequently validated PLK1 and WEE 1 as bona fide therapeutic targets. Small molecule inhibitors of WEE 1 and PLK1 potently inhibited medulloblastoma cell growth and sensitized cells to radiation. In conclusion, using siRNA screens we identified novel therapeutic targets for medulloblastoma therapy Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C83.